Sulfonylurea receptor trangenic rodents

ABSTRACT

The present invention is directed to a method of detecting persistent hyperinsulinemic hypoglycemia of infancy comprising obtaining a sample comprising patient nucleic acids from a patient tissue sample; amplifying sulfonylurea receptor specific nucleic acids from said patient nucleic acids to produce a test fragment; obtaining a sample comprising control nucleic acids from a control tissue sample; amplifying control nucleic acids encoding wild type sulfonylurea receptor to produce a control fragment; comparing the test fragment with the control fragment to detect the presence of a sequence difference in the test fragment, wherein a difference in said test fragment indicates persistent hyperinsulinemic hypoglycemia of infancy. A diagnostic kit and primers for the detection of persistent hyperinsulinemic hypoglycemia of infancy are also within the scope of the present invention.

REFERENCE TO GOVERNMENT GRANTS

This work was supported in part by research grants from the NationalInstitutes of Health, grant number NIH R01DK41898 and R01DK44311. TheUnited States Government may have certain rights in this invention.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.08/404,531, filed Mar. 15, 1995, U.S. Pat. No. 5,863,724, which is acontinuation-in-part of U.S. patent application Ser. No. 08/226,972,filed Apr. 13, 1994, now abandoned, the disclosure of which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Sulfonylureas are oral hypoglycemics widely used in the treatment ofNon-Insulin Dependent Diabetes Mellitus (NIDDM). They enter thebloodstream, bind with high affinity to a pancreatic β-cell plasmamembrane protein termed the sulfonylurea receptor, and stimulate insulinrelease. The mechanism of stimulation is thought to be throughinhibition of an ATP-sensitive K+ channel (K_(ATP)), a key protein whichsets the β-cell resting membrane potential (Ashcroft, et al. Cell.Signal. 1990, 2, 197-214, all references cited herein are incorporatedby reference in their entirety). A reduction in potassium outflow causesdepolarization of the plasma membrane, activation of L-typevoltage-dependent calcium channels (VDCCs), and increased cytosoliccalcium. This triggers insulin release by as yet unknown mechanisms(Rajan, et al. Diabetes Care 1990, 13, 340-363). In NIDDM patients onsulfonylureas, the consequent reduction in blood glucose to more normallevels is thought to be critical in controlling the disease (Gerich, J.E. New Engl. J. Med. 1989, 321, 1231-1245).

The biochemistry of the sulfonylurea receptor (SUR) (Ashcroft et alBiochem. Biophys Acta 1992, 1175, 45-49 and Panten et al. Horm. Metab.Res. 1992, 24, 549-554) is consistent with the electrophysiology of theβ-cell K_(ATP) channel. The endogenous regulators of channel activityinclude cytosolic nucleotides (ATP and Mg-ADP) and possiblyphosphorylation. In the absence of cytosolic nucleotides, sulfonylureasweakly inhibit channel activity (Schwanstecher et al. Br. J. Pharmacol1992, 107, 87-94). When channels are activated by Mg-ADP, inhibition byATP is strongly promoted by the presence of sulfonylureas. These resultsare interpreted as evidence that simultaneous occupancy of twonucleotide binding sites is required for effective channel inhibition bythe sulfonylureas. The reported allosteric interactions correlate wellwith evidence that the brain receptor has two nucleotide binding sites(de Weille, et al. J. Biol. Chem 1992, 267, 4557-4563) physicallylocated on the same polypeptide chain as the sulfonylurea binding site(Bernardi et al. Biochemistry 1992, 31, 6328-6332). One binding siteappears to be specific for ATP, and is proposed to be the same site atwhich micromolar concentrations of ATP inhibit the K_(ATP) channel. Asecond site has high affinity for Mg-ADP, with occupancy at this sitepromoting channel opening. Absolute concentrations of ATP and ADP in thecell are thought to regulate channel activity in a straightforwardfashion (Hopkins et al. J. Membrane Biol. 1992, 129, 287-295). High ATPconcentrations as a result of high serum glucose levels close thechannel, stimulating insulin secretion. Reduced glucose levels increaseintracellular ADP concentrations, and thereby increase the open channelprobability, and decrease insulin secretion.

Although sulfonylureas, particularly tolbutamide and more potent secondgeneration drugs like glyburide and glipizide, are considered to berelatively specific inhibitors of the K_(ATP) channel, the exactrelationship between the sulfonylurea receptor and the K_(ATP) channelis not clear (Nichols et al. Am. J. Physiol. 1991, 261, H1675-H1686,Takano et al. Progress in Neurobiology 1993, 41, 21-30, and Edwards etal. Annu. Rev. Pharmacol. Toxicol. 1993, 33, 597-637). In theinsulin-secreting CRI-G1 cell line, the addition of glyburide, ortolbutamide to inside-out plasma membrane patches inhibits the K_(ATP)channel (Khan et al. Proc. R. Soc. Lond. B. 1993, 253, 225-231),intimating direct interactions between sulfonylureas and the channelprotein. In another insulin secreting cell line, CRI-D11 cells, however,the loss of sulfonylurea binding sites with the retention of K_(ATP)activity suggests these two activities may uncouple and reside onseparate, transiently bound subunits (Khan et al. Proc. R. Soc. Lond. B.1993, 253, 225-231). Similarly, in other cell and tissue types,sulfonylurea binding and channel activity may be uncoupled (Ashford etal Br. J. Pharmac. 1990, 101, 531-540). A technique is not currentlyavailable to assess whether K_(ATP) activity resides within the samepolypeptide containing the putative nucleotide and sulfonylurea bindingsites, or on separate loosely, or tightly bound subunits.

A previous attempt to purify the receptor from hamster insulin-secretingtumor (HIT) cells was limited by the low abundance of the receptor andthe presence of a more abundant co-purifying protein. Aguilar-Bryan, L.,et al., JBC, 1990, 265, 8218.

The sulfonylurea receptor is the target for drugs used in the treatmentof type II diabetes (non-insulin diabetes mellitus). This associationhas suggested it plays a role in the regulation of insulin secretion byglucose and makes the sulfonylurea receptor a potential diabetescandidate gene.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is anautosomal recessive disorder of glucose homeostasis characterized byunregulated secretion of insulin and profound hypoglycemia. A.Aynsley-Green et al., Arch. Dis. Child. 1981, 56, 496. Thepathophysiology of this disease remains obscure, but in vitro studiessuggest a defect of glucose-regulated insulin secretion in pancreaticislet β-cells. Aynsley-Green et al., supra., N. Kaiser et al.,Diabetologia 1990, 33, 482. The incidence of PHHI has been estimated at1/50,000 live births in a randomly mating population. G. J. Bruining,Curr. Opin. Pediatr. 1990, 2, 758. However, in a Saudi Arabianpopulation in which 51% of births occurred to parents who were first orsecond cousins, the incidence has been established as 1/2675 livebirths. P. M. Mathew et al., Clin. Pediatr. 1988, 27, 148. Recently, thePHHI gene was assigned to chromosome 11p1415.1 by linkage analysis. B.Glaser et al., Nature Genet. 1994, 7, 185 and P. M. Thomas, G. J. Cote,D. M. Hallman, P. M. Mathew, Am. J. Hum. Genet. 1995, 56, 416-421.Candidate genes for this disorder include those involved in the β-cellglucose sensing mechanism and insulin secretion. Localization of PHHI tochromosome 11p excluded previously mapped genes involved in β-cellfunction. Considered as a candidate was the newly cloned high-affinitySUR gene, a member of the ATP-binding cassette superfamily, and aputative subunit of the modulator of insulin secretion, the β-cellATP-sensitive potassium channel (K_(ATP)). S. J. Ashcroft and F. M.Ashcroft, Biochimica et Biophysica Acta, 1992, 1175, 45; U. Panten, M.Schwanstecher, and C. Schwanstecher, Horm. Metab. Res. 1992, 24, 549.The methods of the present invention map the sulfonylurea receptor tothe same chromosomal location as PHHI and provide evidence thatmutations in the sulfonylurea receptor are the cause of PHHI.

Accordingly, there remains a need to identify sulfonylurea receptor andsequences encoding sulfonylurea receptor which will provide:

1. a correlation between sulfonylurea receptor and one or more forms ofdiabetes,

2. a sequence to purify human sulfonylurea receptors,

3. an isolated sulfonylurea receptor, prepared by recombinant methods,

4. polyclonal and monoclonal antibodies and methods of preparing thesame against sulfonylurea receptor,

5. information as to whether this receptor-ion channel family involvesmulti-subunits within each channel for channel activity,

6. gene therapy such that sequences which encode mutant sulfonylureareceptors are replaced by wild type sulfonylurea receptor sequences,

7. a method of screening to identify drugs which react with and bind tothe sulfonylurea receptor,

8. non-human transgenic animals to study diabetes and PHHI, and thephysiologic effects of varying levels of sulfonylurea receptor, by usingan inducible promoter to regulate the expression of the sulfonylureareceptor, for example, and

9. probes, including PCR probes, for diagnosing conditions associatedwith the expression of a specific sulfonylurea receptor allele.

The present invention reveals that the sequence encoding the mammaliansulfonylurea receptor maps to the sequence encoding persistenthyperinsulinemic hypoglycemia of infancy.

SUMMARY OF THE INVENTION

The present invention provides sequences encoding a sulfonylureareceptor. Nucleic acid sequences, SEQ ID NOS: 4, 5, 7, and 9 are cDNAsequences to which the present invention is directed. SEQ ID NOS: 4, 5,7, and 9 are rodent sequences (SEQ ID NOS: 4 and 5--rat, SEQ ID NOS: 7and 9--hamster) encoding sulfonylurea receptor which functionally bindsulfonylurea. SEQ ID NOS: 1 and 2 are human sequences which encodesulfonylurea receptor. SEQ ID NOS: 2, 5, and 8 set forth DNA sequencestranslated into amino acid sequences, which set forth below the DNAsequence.

A further aspect of the present invention provides sulfonylurea receptorpolypeptides and/or proteins. SEQ ID NOS:2, 3, 5, 6, 8, and 9 are novelpolypeptides of the invention produced from nucleotide sequencesencoding rat (SEQ ID NOS: 5 and 6), hamster (SEQ ID NOS: 8 and 9), andhuman (SEQ ID NOS: 2 and 3) sulfonylurea receptor, respectively. Alsowithin the scope of the present invention is a purified sulfonylureareceptor.

The present invention also provides nucleic acid sequences encoding asulfonylurea receptor, expression vectors comprising a nucleic acidsequence encoding a sulfonylurea receptor, transformed host cellscapable of expressing a nucleic acid sequence encoding a sulfonylureareceptor, cell cultures capable of expressing a sulfonylurea receptor,and protein preparations comprising a sulfonylurea receptor.

A method of detecting persistent hyperinsulinemic hypoglycemia ofinfancy comprising obtaining a sample comprising patient nucleic acidsfrom a patient tissue sample; amplifying sulfonylurea receptor specificnucleic acids from said patient nucleic acids to produce a testfragment; obtaining a sample comprising control nucleic acids from acontrol tissue sample; amplifying control nucleic acids encoding wildtype sulfonylurea receptor to produce a control fragment; comparing thetest fragment with the control fragment to detect the presence of asequence difference in the test fragment, wherein a difference in saidtest fragment indicates persistent hyperinsulinemic hypoglycemia ofinfancy is also an embodiment of the present invention.

Other methods of the present invention include a method of detectingpersistent hyperinsulinemic hypoglycemia of infancy comprising obtaininga sample comprising patient mRNA from a patient tissue sample; reversetranscribing said mRNA into cDNA to produce patient cDNA; amplifyingsulfonylurea receptor specific cDNA from said patient cDNA to produceamplified patient cDNA; obtaining a sample comprising control nucleicacids from a control tissue sample; amplifying control DNA encoding wildtype sulfonylurea receptor to produce control cDNA; digesting said testfragment and said control fragment with a selected endonuclease; andcomparing the test fragment to the control fragment, wherein said testfragment indicates persistent hyperinsulinemic hypoglycemia of infancy.

Another embodiment of the present invention is a diagnostic kit fordetecting persistent hyperinsulinemic hypoglycemia of infancy comprisingin one or more containers a pair of primers, wherein one primer withinsaid pair is complementary to a region of the sulfonylurea receptor,wherein one of said pair of primers is selected from the groupconsisting of SEQ ID NOS: 12-20, a probe specific to the amplifiedproduct, and a means for visualizing amplified DNA, such as and notlimited to fluorescent stain, ³² P, and biotin, and optionally includingone or more size markers, positive and negative controls, andrestriction endonucleases.

Still another embodiment of the present invention includes the primersequences identified in SEQ ID NOS: 12-20.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B display characteristics of the purified HIT cellreceptor. The radiolabeled receptor (lanes 1 and 3) cleaved withendoglycosidase F/N-glycosidase F (endo F), increases the mobility ofthe protein by approximately 3 kDa (lane 2). Subsequent partial V8protease digestion (lanes 4 and 6) yielded radiolabeled fragments thatalso shift mobility with endo F treatment (lane 5). Each of thesespecies has the same N-terminal sequence (left side of figure), exceptthat receptor deglycosylation results in an Asp at residue 9.

FIG. 2A shows that antibodies against residues 10-20 specificallyrecognize the 140 kDa polypeptide. Purified 140 kDa polypeptide waselectrophoresed on a single lane of a 6% SDS gel and transferred toImmobilon P. The Immobilon P was placed in a miniblotter and the lanesincubated as follows: Lane 1--Preimmune serum. Lane 2--Immune serum.Lane 3--Immune serum+immunogen. Lane 4--immune serum+irrelevant MAPpeptide. The filter was further incubated with a second antibody (goatanti-rabbit conjugated to alkaline phosphatase) and developed with theappropriate substrates. FIG. 2B displays antibodies which recognize apolypeptide with the appropriate mobility shift following Endo Ftreatment. Purified receptor (lane 1) was incubated for 30 min at 37° C.in the presence (lane 2), or absence (lane 3) of endoglycosidaseF/N-glycosidase F, incubated with first (anti-MAP 10-20) and secondantibody, and developed with substrate. The bottom panel shows theautoradiogram of the immunoblot in the top panel. FIG. 2C showsantibodies which immunoprecipitate the photolabeled 140 kDa receptor.HIT cell membranes were incubated with ¹²⁵ I-labeled iodoglyburide,photolabeled, solubilized with 1% digitonin, centrifuged at 100,000×gand the supernatant (lane 1) incubated with preimmune serum (lane 2),immune serum (lane 3), immune serum+anti-MAP 10-20 (lane 4) and immuneserum+irrelevant MAP peptide (lane 5). Samples were co-incubated withprotein A-Sepharose, the beads washed with buffer, heated in thepresence of pH 9 sample buffer, electrophoresed on a 6% polyacrylamideSDS gel, and an autoradiogram prepared. Results using antibodies againstreceptor residues 1-8 were the same as those using antibodies againstresidues 10-20.

Multiple antigenic peptides (MAPS) were synthesized (Posnett et al. J.Biol. Chem. 1988 263:1719-1725) and polyclonal antibodies generated inrabbits produced by standard methods (Antibodies: A Laboratory ManualCold Spring Harbor Laboratory 1988). Interdermal injections of 1 mg ofantigen were spaced 2-3 weeks apart, and contained complete, orincomplete Freund's adjuvant.

FIG. 3 is a northern blot of total RNA from α- and β-cell lineshybridized with a 2.2 kb EcoRI-Xhol fragment of the sulfonylureareceptor. Approximately 10 μg of RNA from (A) αTC-6 cells, (B) HITcells, (C) RIN cells and (D) mouse liver was analyzed using standardprocedures (Ausubel et al. Current Protocols in Mol. Biol. 1994). Theestimated size of the major component is approximately 5000 nucleotides.

FIG. 4 displays a hydrophobicity profile of the Rat Sulfonylureareceptor. Hydrophobicity values were determined according to Kyte andDoolittle (Kyte et al. J. Mol. Biol. 1982 157:105-132) for 11-residuepeptides and are plotted versus the amino acid number. The bars marked Aand B are over the Walker A and B consensus sequences Walker et al. EMBOJour. 1982 1:945-951).

FIG. 5 shows a schematic model of the high affinity sulfonylureareceptor. The Walker A and B sites are marked within the two nucleotidebinding folds. Based on the hydrophobicity and hydrophobic moment datathere are nine transmembrane spanning domains before the firstnucleotide binding fold and four transmembrane spanning domains betweenthe two folds. The branched structure at the N-terminus of the maturereceptor symbolizes glycosylation.

FIG. 6A reveals the results of in vitro translation of mRNA transcribedfrom the rat sulfonylurea cDNA. The cDNA was subcloned into pGEM4(Promega, Inc., Madison, Wis.) and transcribed using the SP6 promoterand SP6 RNA polymerase following the manufacturer's directions. RNA wastranslated in rabbit reticulocyte lysate (Promega, Inc.) following themanufacturer's recommendations for ³⁵ S-methionine. Lane 1 is the HITcell photolabeled receptor as a marker, lane 2 is the in vitrotranslation product resulting from addition of receptor mRNA and lane 3is the result of no added RNA. The arrow marks the 140 kDa protein.

FIG. 6B displays a gel of the results of immunoprecipitation of the RINcell sulfonylurea receptors with polyclonal antibodies directed againsta nucleotide binding fold domain (NBF). Lane 1; 140 and 150 kDareceptors from soluble RIN cell membrane proteins, lane 2;immunoprecipitation with preimmune serum, lane 3; immune serum fromrabbit immunized with NBF2, lane 4; immune serum+NBF2 fusion protein.Sulfonylurea receptor cDNA regions encoding the NBF2 domain wassubcloned in frame into pMALc and expression of the proteins fused withmaltose binding protein induced in E. coli. Fusion proteins werepurified by electrophoresis and electroelution, and 200μg amounts, withcomplete, or incomplete Freund's adjuvant, injected interdermally intorabbits using a standard 2-3 week regimen of bleeding and boosting.

FIG. 7 displays the genomic organization and cDNA sequence of the humansulfonylurea receptor (SUR) homologue in the second nucleotide bindingfragment region (NBF-2). The sequence encoding NBF-2 is located withinSEQ ID NO: 1, nucleic acid positions 524 to 1048. Solid rectanglesrepresent exons which are labeled α-φ for identification. The numbersbetween rectangles represent intronic sizes. Primers used in mutationalanalysis are diagrammed and listed in SEQ ID NOS: 12-20.

FIGS. 8A-D display the exon mutation in the SUR NBF-2. FIG. 8A is aschematic representation of NBF-2 exons β, X, δ illustrating the normal(upper) and mutant (lower) RNA splicing patterns. FIG. 8B displays thesequence of a pancreatic cDNA product, from an affected child of Family6, demonstrating the exon skipping event. Skipping of exon X results ina 109 bp deletion in the mRNA transcript, a frame shift and inclusion ofa premature stop codon. Single upper case letters represent amino acids.FIG. 8C shows the sequence of genomic DNA from the affected patient inFIG. 8B which reveals a G to A point mutation at the 3' end of the exon,which exon is excised in mRNA, as compared to a normal sample of genomicDNA. Exonic sequence is in upper case and intronic sequence in lowercase letters. FIG. 8D shows Mspl restriction enzyme analysis ofPCR-amplified genomic DNA from members of Family 6, indicating affectedindividuals. The G to A mutation destroyed a restriction site for Mspl(C/CGG). Normal PCR product is digested into 304 bp, 85 bp, and 38 bpfragments, while that containing the mutation is digested into 304 bpand 123 bp fragments. MW is 100 bp ladder (GIBCO-BRL, Gaithersburg,Md.), UC is an uncut sample, C is a control PCR reaction lackingtemplate.

FIGS. 9A-D reveal a mutation in the intron preceding NBF-2 exon α, whichactivates cryptic 3' splice site usage. FIG. 9A displays the sequence ofgenomic DNA from an affected member of Family 4 which revealed a G to Amutation in the splice site preceding the first exon of the NBF-2. FIG.9B shows Ncil restriction enzyme analysis of genomic DNA from members ofFamily 4, indicating affected individuals. The G to A mutation destroysa restriction site for Ncil (CC/(G/C)GG). Normal PCR product is digestedinto 71 bp and 75 bp fragments, while that containing the mutantsequence is not cut. By previous haplotype analysis, the unaffectedsibling in this family had two wild type alleles, P. M. Thomas, G. J.Cote, D. M. Hallman, P. M. Mathew, Am. J. Hum. Genet., supra. FIG. 9Cillustrates the constructs used to examine RNA processing of exonswithin NBF-2. Solid rectangles and thin lines represent human SUR geneexonic and intronic sequences, respectively. The unmarked solidrectangle represents a portion of the exon which is 5' to exon a of theNBF-2 region. That labeled RSV represents the enhancer and promoterisolated from the rous sarcoma virus long terminal repeat. The thickline represents an intronic sequence derived from vector and the humanmetallothionine IIA gene, which also contains polyadenylation signals.Normal and mutant RNA splicing patterns, including the location of thethree cryptic splice sites, are diagrammed in the lower portion. Theopen triangle marks the position of the mutated base within the splicesite. FIG. 9D shows PCR amplification across splice site of normal (N)and mutant (M) cDNA transcripts, isolated 48 hours after transfectionwith the splicing constructs. Subcloning and sequencing of theseproducts revealed their identity as diagrammed in FIG. 9C. The control(C) represents cDNA amplified from untransfected cells.

FIG. 10 depicts pCR™ 11 vector.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the nucleic acid and proteinsequences encoding a sulfonylurea receptor. The present inventionprovides nucleotide sequences of a sulfonylurea receptor, and SEQ IDNOS: 1, 2, 4, 5, 7, and 8. Novel polypeptide sequences, SEQ ID NOS: 2,3, 5, 6, 8, and 9 coding for a sulfonylurea receptor are also includedin the present invention. SEQ ID NOS: 1-3 provide the nucleic acid andamino acid sequences of the last 11 exons of the 3' end of humansulfonylurea receptor, respectively, hereinafter referred to, togetherwith the rodent sequences for sulfonylurea receptor, as sequence for thesulfonylurea receptor.

SEQ ID NOS: 5 and 8 provide the cDNA sequences of rodent sulfonylureareceptor. SEQ ID NOS: 1 and 2 provide the human cDNA and genomic DNAsequence of sulfonylurea receptor, respectively. Nucleic acids within inthe scope of the present invention include cDNA, RNA, genomic DNA,sequences within these larger sequences, antisense oligonucleotides.Sequences encoding the sulfonylurea receptor also include amino acid,polypeptide, and protein sequences. Variations in the nucleic acid andpolypeptide sequences of the present invention are within the scope ofthe present invention and include N terminal and C terminal extensions,transcription and translation modifications, and modifications in thecDNA sequence to facilitate and improve transcription and translationefficiency. In addition, mismatches within the sequences identifiedherein, which achieve the methods of the invention, such that themismatched sequences are substantially complementary to the sulfonylureareceptor sequences identified, are also considered within the scope ofthe present invention. Mismatches which permit substantialcomplementarity to the sulfonylurea receptor sequences, such assimilarity in residues in hydrophobicity, will be known to those ofskill in the art once armed with the present disclosure. In addition,the sequences of the present invention may be natural or synthetic.

A purified sulfonylurea receptor is also provided by the presentinvention. The purified sulfonylurea receptor may have an amino acidsequence as provided by SEQ ID NOS: 2, 3, 5, 6, 8, and 9.

The present invention is directed to sulfonylurea receptor sequencesobtained from mammals from the Order Rodentia, including and not limitedto hamsters, rats, and mice; Order Logomorpha, such as rabbits; moreparticularly the Order Carnivora, including Felines (cats) and Canines(dogs); even more particularly the Order Artiodactyla, Bovines (cows)and Suines (pigs); and the Order Perissodactyla, including Equines(horses); and most particularly the Order Primates, Ceboids and Simoids(monkeys) and Anthropoids (humans and apes). The mammals of mostpreferred embodiments are humans.

There are several transfection techniques by which a sulfonylureareceptor may be obtained. An appropriate RNA may be hybridized to a cDNAto obtain a sulfonylurea receptor nucleic acid sequence. A nucleic acidsequence encoding sulfonylurea receptor may be inserted into cells andthe corresponding protein immunoprecipitated with an antibody. Labeleddrugs known to bind sulfonylurea receptor protein may be added to cellculture to label the receptor. The drug labeling procedure may involvemodifying cells such that the cell culture provides conditions similarto β cells, cells where sulfonylurea receptors naturally appear; and thesulfonylurea receptor may be part of a larger multisubunit ATP receptorchannel, which may not be provided by the cells in culture.

Generally, the sequences of the invention may be produced in host cellstransformed with an expression vector comprising a nucleic acid sequenceencoding the sulfonylurea receptor. The transformed cells are culturedunder conditions whereby the nucleic acid sequence coding for thesulfonylurea receptor is expressed. After a suitable amount of time forthe protein to accumulate, the protein is purified from the transformedcells.

A gene coding for sulfonylurea receptor may be obtained from a cDNAlibrary. Suitable libraries can be obtained from commercial sources suchas Clontech, Palo Alto, Calif. Libraries may also be prepared using thefollowing non-limiting examples hamster insulin-secreting tumor (HIT),mouse αTC-6, and rat insulinoma (RIN) cells. Positive clones are thensubjected to DNA sequencing to determine the presence of a DNA sequencecoding for sulfonylurea receptor. DNA sequencing is accomplished usingthe chain termination method of Sanger et al., Proc. Nat'l. Acad. Sci,U.S.A., 1977, 74, 5463. The DNA sequence encoding sulfonylurea receptoris then inserted into an expression vector for later expression in ahost cell.

Expression vectors and host cells are selected to form an expressionsystem capable of synthesizing sulfonylurea receptor. Vectors includingand not limited to baculovirus vectors may be used in the presentinvention. Host cells suitable for use in the invention includeprokaryotic and eukaryotic cells that can be transformed to stablycontain and express sulfonylurea receptor. For example, nucleic acidcoding for the recombinant protein may be expressed in prokaryotic oreukaryotic host cells, including the most commonly used bacterial hostcell for the production of recombinant proteins, E. coli. Othermicrobial strains may also be used, however, such as Bacillus subtilis,and other enterobacteriaceae such as Salmonella typhimurium or Serratiamarcescens, various species of Pseudomonas, or other bacterial strains.

Commonly used eukaryotic systems include yeast, such as Saccharomycescerevisiae; insect cells, such as Spodoptera frugiperda; chicken cells,such as E3C/O and SL-29; mammalian cells, such as HeLa, Chinese hamsterovary cells (CHO), COS-7 or MDCK cells and the like. The foregoing listis illustrative only and is not intended in any way to limit the typesof host cells suitable for expression of the nucleic acid sequences ofthe invention.

As used herein, expression vectors refer to any type of vector that canbe manipulated to contain a nucleic acid sequence coding forsulfonylurea receptor, such as plasmid expression vectors and viralvectors. The selection of the expression vector is based oncompatibility with the desired host cell such that expression of thenucleic acid encoding sulfonylurea receptor results. Plasmid expressionvectors comprise a nucleic acid sequence of the invention operablylinked with at least one expression control element such as a promoter.In general, plasmid vectors contain replicon and control sequencesderived from species compatible with the host cell. To facilitateselection of plasmids containing nucleic acid sequences of theinvention, plasmid vectors may also contain a selectable marker such asa gene coding for antibiotic resistance. Suitable examples include thegenes coding for ampicillin, tetracycline, chloramphenicol or kanamycinresistance.

Suitable expression vectors, promoters, enhancers, and other expressioncontrol elements are known in the art and may be found in Sambrook etal., Molecular Cloning: A Laboratory Manual, second edition, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y. (1989), incorporatedherein by reference in its entirety.

Transformed host cells containing a DNA sequence encoding sulfonylureareceptor may then be grown in an appropriate medium for the host. Thecells are then grown until product accumulation reaches desired levelsat which time the cells are then harvested and the protein productpurified in accordance with conventional techniques. Suitablepurification methods include, but are not limited to, SDS PAGEelectrophoresis, phenylboronate-agarose, reactive green 19-agarose,concanavalin A sepharose, ion exchange chromatography, affinitychromatography, electrophoresis, dialysis and other methods ofpurification known in the art.

Protein preparations, of purified or unpurified sulfonylurea receptorproduced by host cells, are accordingly produced which comprisesulfonylurea receptor and other material such as host cell componentsand/or cell medium, depending on the degree of purification of theprotein.

Antibodies, including and not limited to monoclonal, polyclonal, andchimeric, prepared and used against a sulfonylurea receptor are alsowithin the scope of the present invention, and may be prepared bymethods known to those of skill in the art such as and not limited tothe methods of Kohler and Milstein, Nature, 256: 495-497 (1975),incorporated herein by reference in its entirety.

The invention also includes a transgenic non-human animal, including andnot limited to mammals, such as and not limited to a mouse, rat, orhamster, whose germ cells and somatic cells contain a sequence encodinga sulfonylurea receptor introduced into the animal or an ancestor of theanimal. The sequence may be wild-type or mutant and may be introducedinto the animal at the embryonic or adult stage. The sequence isincorporated into the genome of an animal such that it is chromosomallyincorporated into an activated state. Embryo cells may be transfectedwith the gene as it occurs naturally, and transgenic animals areselected in which the gene has integrated into the chromosome at a locuswhich results in activation. Other activation methods include modifyingthe gene or its control sequences prior to introduction into the embryo.The embryo may be transfected using a vector containing the gene.

In addition, a transgenic non-human animal may be engineered wherein thesulfonylurea receptor is suppressed. For purposes of the presentinvention, suppression of the sulfonylurea receptor includes, and is notlimited to strategies which cause the sulfonylurea receptor not to beexpressed. Such strategies may include and are not limited to inhibitionof protein synthesis, pre-mRNA processing, or DNA replication. Each ofthe above strategies may be accomplished by antisense inhibition ofsulfonylurea receptor gene expression. Many techniques for transferingantisense sequences into cells are known to those of skill, includingand not limited to microinjection, viral-mediated transfer, somatic celltransformation, transgene integration, and the like, as set forth inPinkert, Carl, Transgenic Animal Technology, 1994, Academic Press, Inc.,San Diego, Calif., incorporated herein by reference in its entirety.

Further, a transgenic non-human animal may be prepared such that thesulfonylurea receptor gene is knocked out. For purposes of the presentinvention, a knock out includes and is not limited to disruption orrendering null the sulfonylurea receptor gene. A knock out may beaccomplished, for example, with antisense sequences for the sulfonylureareceptor mutating the sequence for the sulfonylurea receptor. Thesulfonylurea receptor gene may be knocked out by injection of anantisense sequence for all or part of the sulfonylurea receptor sequencesuch as an antisense sequence for all or part of SEQ ID NO: 2. Once thesulfonylurea receptor has been rendered null, correlation of thesulfonylurea receptor to persistent hyperinsulinemic hypoglycemia ofinfancy may be tested. Sequences encoding mutations affecting thesulfonylurea receptor may be inserted to test alterations in glucosehomeostasis.

Also in transgenic non-human animals, the sulfonylurea receptor may bereplaced by preparing a construct having an insulin promoter ligated tothe sulfonylurea receptor gene. This experiment permits testing ofmutant sulfonylurea receptors directly in the pancreas of the transgenicanimal.

Transgenic non-human animals may also be useful for testing nucleic acidchanges to identify nucleotides which are responsible for ADP and ATPmodulation of the sulfonylurea receptor resulting in an increase ordecrease in glucose sensitivity of insulin release.

The present invention is also directed to gene therapy wherein a mutantsulfonylurea receptor is replaced by a wild type sulonylurea receptor. Aresulting transgenic non-human animal thus comprises a recombinantsulfonylurea receptor. In addition, gene therapy techniques may be usedfor individuals with persistent hyperinsulinemic hypoglycemia ofinfancy. For purposes of the present invention, gene therapy refers tothe transfer and stable insertion of new genetic information into cellsfor the therapeutic treatment of diseases or disorders. The foreign geneis transferred into a cell that proliferates to spread the new genethroughout the cell population. Known methods of gene transfer includemicroinjection, electroporation, liposomes, chromosome transfer,transfection techniques, calcium-precipitation transfection techniques,and the like.

Numerous techniques are known in the art for the introduction of foreigngenes into cells and may be used to construct the recombinant cells forpurposes of gene therapy, in accordance with this embodiment of theinvention. The technique used should provide for the stable transfer ofthe heterologous gene sequence to the stem cell, so that theheterologous gene sequence is heritable and expressible by stem cellprogeny, and so that the necessary development and physiologicalfunctions of the recipient cells are not disrupted. Techniques which maybe used include but are not limited to chromosome transfer (e.g., cellfusion, chromosome-mediated gene transfer, micro cell-mediated genetransfer), physical methods (e.g., transfection, spheroplast fusion,microinjection, electroporation, liposome carrier), viral vectortransfer (e.g., recombinant DNA viruses, recombinant RNA viruses) andthe like (described in Cline, M. J., 1985, Pharmac. Ther. 29:69-92,incorporated herein by reference in its entirety).

The term "purified", when used to describe the state of nucleic acidsequences of the invention, refers to nucleic acid sequencessubstantially free of nucleic acid not coding for sulfonylurea receptoror other materials normally associated with nucleic acid innon-recombinant cells, i.e., in its "native state."

The term "purified" or "in purified form" when used to describe thestate of a sulfonylurea receptor, protein, polypeptide, or amino acidsequence, refers to sulfonylurea receptor sequences free, to at leastsome degree, of cellular material or other material normally associatedwith it in its native state. Preferably the sequence has a purity(homogeneity) of at least about 25% to about 100%. More preferably thepurity is at least about 50%.

To begin to elucidate the relationship between the sulfonylurea receptorand K_(ATP), the iodinated derivative of glyburide was used to identify,and subsequently to purify and obtain N-terminal amino acid sequencefrom the 140 kDa high affinity, hamster insulin-secreting tumor (HIT)cell sulfonylurea receptor. The peptide sequence data was used to clonefull length cDNAs encoding the rat and hamster β-cell proteins of thepresent invention.

Another embodiment of the present invention is a method of detectingpersistent hyperinsulinemic hypoglycemia of infancy comprising obtaininga sample comprising patient nucleic acids from a patient tissue sample;amplifying sulfonylurea receptor specific nucleic acids from saidpatient nucleic acids to produce a test fragment; obtaining a samplecomprising control nucleic acids from a control tissue sample;amplifying control nucleic acids encoding wild type sulfonylureareceptor to produce a control fragment; comparing the test fragment withthe control fragment to detect the presence of a sequence difference inthe test fragment, wherein a difference in said test fragment indicatespersistent hyperinsulinemic hypoglycemia of infancy is also anembodiment of the present invention.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is anautosomal recessive disorder which results in unregulated insulinsecretion. The present invention revealed several different mutations inthe sulfonylurea receptor in individuals with PHHI. These mutationsinclude nucleic acid transition and restriction fragment lengthpolymorphism, both defined herein as sequence differences. The nucleicacid sequence transition may be a G to A transition at nucleic acidposition 750 in SEQ ID NO: 1 which results in PHHI. This transition wasfound to occur in nine affected children in nine different families ofthe families studied. The pancreatic cDNA from a child with thistransition involved skipping an exon. Genomic DNA template was amplifiedto obtain the product for Msp I digestion for testing and confirmationof the mutation at position 750 in SEQ ID NO: 1. When cDNA is amplified,the Msp I restriction site is not present. Exon X of FIG. 7 was skippedresulting in an mRNA transcript having a 109 bp deletion, a frame shift,and the inclusion of a premature stop codon. This deletion may be seenby performing rtPCR on the child's mRNA. Amplification of SEQ ID NO: 1with primer sequences of SEQ ID NOS: 18 and 20 resulted in a 427 basepair product for the normal as well as for the mutant cDNA. Digestingthe normal and mutant products with MspI, however, resulted in threefragments (304 bp, 85 bp, and 38 bp) for the normal gene and twofragments (304 bp and 123 bp) for the mutant gene of affected children.

Another mutation involves a G to A transition in intron 11 of the humansulfonylurea receptor which gives rise to PHHI. The transition sitecorresponds to position 27 of SEQ ID NO: 31. The G to A transitiondestroys a restriction site for NciI. Both normal and mutant PCRproducts resulted in 146 bp. Digestion with NciI resulted in twofragments (71 bp and 75 bp) fragments for normal individuals, while themutant sequence was not be cut by NciI and thus remained at 146 bp.

A method of detecting persistent hyperinsulinemic hypoglycemia ofinfancy comprising obtaining a sample comprising patient genomic DNAfrom a patient tissue sample; amplifying sulfonylurea receptor specificDNA from said patient genomic DNA to produce a test fragment; obtaininga sample comprising control nucleic acids from a control tissue sample;amplifying control DNA encoding wild type sulfonylurea receptor toproduce a control fragment; comparing the test fragment with the controlfragment to detect a test fragment having G to A transition at nucleicacid position 750 of SEQ ID NO: 1, or a G to A transition at nucleicacid position 27 of SEQ ID NO: 31, wherein said test fragment indicatespersistent hyperinsulinemic hypoglycemia of infancy is also anembodiment of the present invention.

Also within the scope of the present invention is a method of detectingpersistent hyperinsulinemic hypoglycemia of infancy comprising obtaininga sample comprising patient genomic DNA from a patient tissue sample;amplifying sulfonylurea receptor specific DNA from said patient genomicDNA to produce a test fragment; obtaining a sample comprising controlnucleic acids from a control tissue sample; amplifying control DNAencoding wild type sulfonylurea receptor to produce a control fragment;digesting said test fragment and said control fragment with anendonuclease selected from the group consisting of NciI and MspI; andcomparing the test fragment with the control fragment to detect arestriction fragment length polymorphism, wherein said restrictionfragment length polymorphism indicates persistent hyperinsulinemichypoglycemia of infancy.

The restriction fragment polymorphisms include test fragments of about304 bp and about 123 bp as a result of MspI restriction and a testfragment of about 146 bp as a result of NciI restriction using primersequences of SEQ ID NOS: 18 and 20. The test fragments thus indicatepersistent hyperinsulinemic hypoglycemia of infancy.

In accordance with methods of the present invention, methods ofdetecting PHHI in a patient are provided comprising obtaining a patienttissue sample for testing. The tissue sample may be solid or liquid, abody fluid sample such as and not limited to blood, serum, saliva,sputum, mucus, bone marrow, urine, lymph, and a tear; and feces. Inaddition, a tissue sample such as pancreatic tissue may be provided forthe detection of PHHI in accordance with the present invention.

A test fragment is defined herein as an amplified sample comprisingsulfonylurea receptor specific nucleic acids from a patient suspected ofhaving PHHI. A control fragment is an amplified sample comprising normalor wild type sulfonylurea receptor specific nucleic acids from anindividual not suspected of having PHHI.

The method of amplifying nucleic acids may be the polymerase chainreaction using a pair of primers wherein at least one primer within thepair is selected from the group consisting of SEQ ID NO: 12-20. When thepolymerase chain reaction is the amplification method of choice, a pairof primers may be used such that one primer of the pair is selected fromthe group consisting of SEQ ID NOS: 13, 14, 17, and 19 and the secondprimer of the pair is selected from the group consisting of SEQ ID NOS:12, 15, 16, 18, and 20.

Nucleic acids, such as DNA (such as and not limited to genomic DNA andcDNA) and/or RNA (such as and not limited to mRNA), are obtained fromthe patient sample. Preferably RNA is obtained. A whole blood gradientmay be performed to isolate nucleated cells and total RNA is extractedsuch as by the RNazole B method (Tel-Test Inc., Friendswood, Tex.) or bymodification of any methods known in the art such as described inSambrook et al., Molecular Cloning: A Laboratory Manual, 1989, ColdSpring Harbor Laboratory, Cold Spring Harbor, N.Y., incorporated hereinby reference in its entirety.

Nucleic acid extraction is followed by amplification of the same by anytechnique known in the art. The amplification step includes the use ofat least one primer sequence which is complementary to a portion ofsulfonylurea receptor specific expressed nucleic acids or sequences.Primer sequences useful in the amplification methods include and are notlimited to SEQ ID NOS: 12-20, which may be used in the amplificationmethods. Any primer sequence of about 10 nucleotides to about 35nucleotides, more preferably about 15 nucleotides to about 30nucleotides, even more preferably about 17 nucleotides to about 25nucleotides may be useful in the amplification step of the methods ofthe present invention. In addition, mismatches within the sequencesidentified above, which achieve the methods of the invention, such thatthe mismatched sequences are substantially complementary and thushybridizable to the sequence sought to be identified, are alsoconsidered within the scope of the disclosure. Mismatches which permitsubstantial similarity to SEQ ID NOS: 12-20, such as and not limited tosequences with similar hydrophobicity and hydrophilicity, will be knownto those of skill in the art once armed with the present disclosure. Theprimers may also be unmodified or modified. Primers may be prepared byany method known in the art such as by standard phosphoramiditechemistry. See Sambrook et al., supra.

The method of amplifying nucleic acids may be the polymerase chainreaction using a pair of primers wherein at least one primer within thepair is selected from the group consisting of SEQ ID NO: 12-20. When thepolymerase chain reaction is the amplification method of choice, a pairof primers may be used such that one primer of the pair is selected fromthe group consisting of SEQ ID NOS: 12-20.

Primers used in mutational analysis were SEQ ID NO: 12:CACGCTCAGGTTCTGGAT; SEQ ID NO: 13: TCAACTGGATGGTGAGGA; SEQ ID NO: 14: 5'TGACATCGCCAAACTGC; SEQ ID NO: 15: TCCTGGCAGTGCCTTCA; SEQ ID NO: 16:TCCTCTCAGGGTCCAGGTTA; SEQ ID NO: 17: ACAAGGAGCCTGGGGAT; SEQ ID NO: 18:TGCATGGGTCCCAGTGA; SEQ ID NO: 19: TTGACCATTCACCACATTGGTGTGC; and SEQ IDNO: 20: TCCTGGCAGTGCCTTCA.

When an amplification method includes the use of two primers, a firstprimer and a second primer, such as in the polymerase chain reaction,the first primer may be selected from the group consisting of SEQUENCEID NOS: 13, 14, 17, and 19; and the second primer may be selected fromthe group consisting of SEQUENCE ID NOS: 12, 15, 16, 18, and 20. Anyprimer pairs which transcribe nucleic acids toward each other and whichare specific for sulfonylurea receptor may be used in accordance withthe methods of the present invention.

Total extraction of RNA is preferably carried out. As used herein, theterm "amplification" refers to template-dependent processes andvector-mediated propagation which result in an increase in theconcentration of a specific nucleic acid molecule relative to itsinitial concentration, or in an increase in the concentration of adetectable signal. As used herein, the term template-dependent processis intended to refer to a process that involves the template-dependentextension of a primer molecule. The term template dependent processrefers to nucleic acid synthesis of an RNA or DNA molecule wherein thesequence of the newly synthesized strand of nucleic acid is dictated bythe well-known rules of complementary base pairing (see, for example,Watson, J. D. et al., In: Molecular Biology of the Gene, 4th Ed., W. A.Benjamin, Inc., Menlo Park, Calif. (1987)). Typically, vector mediatedmethodologies involve the introduction of the nucleic acid fragment intoa DNA or RNA vector, the clonal amplification of the vector, and therecovery of the amplified nucleic acid fragment. Examples of suchmethodologies are provided by Cohen et al. (U.S. Pat. No. 4,237,224),Maniatis, T. et al., Molecular Cloning (A Laboratory Manual), ColdSpring Harbor Laboratory, 1982.

A number of template dependent processes are available to amplify thetarget sequences of interest present in a sample. One of the best knownamplification methods is the polymerase chain reaction (PCR) which isdescribed in detail in U.S. Pat. Nos. 4,683,195, 4,683,202 and4,800,159, and in Innis et al., PCR Protocols, Academic Press, Inc., SanDiego Calif., 1990, each of which is incorporated herein by reference inits entirety. Briefly, in PCR, two primer sequences are prepared whichare complementary to regions on opposite complementary strands of thetarget sequence. An excess of deoxynucleoside triphosphates are added toa reaction mixture along with a DNA polymerase (e.g., Taq polymerase).If the target sequence is present in a sample, the primers will bind tothe target and the polymerase will cause the primers to be extendedalong the target sequence by adding on nucleotides. By raising andlowering the temperature of the reaction mixture, the extended primerswill dissociate from the target to form reaction products, excessprimers will bind to the target and to the reaction products and theprocess is repeated. Preferably a reverse transcriptase PCRamplification procedure may be performed in order to quantify the amountof mRNA amplified. Polymerase chain reaction methodologies are wellknown in the art.

Another method for amplification is the ligase chain reaction (referredto as LCR), disclosed in EPA No. 320,308, incorporated herein byreference in its entirety. In LCR, two complementary probe pairs areprepared, and in the presence of the target sequence, each pair willbind to opposite complementary strands of the target such that theyabut. In the presence of a ligase, the two probe pairs will link to forma single unit. By temperature cycling, as in PCR, bound ligated unitsdissociate from the target and then serve as "target sequences" forligation of excess probe pairs. U.S. Pat. No. 4,883,750, incorporatedherein by reference in its entirety, describes an alternative method ofamplification similar to LCR for binding probe pairs to a targetsequence.

Qbeta Replicase, described in PCT Application No. PCT/US87/00880,incorporated herein by reference in its entirety, may also be used asstill another amplification method in the present invention. In thismethod, a replicative sequence of RNA which has a region complementaryto that of a target is added to a sample in the presence of an RNApolymerase. The polymerase will copy the replicative sequence which canthen be detected.

An isothermal amplification method, in which restriction endonucleasesand ligases are used to achieve the amplification of target moleculesthat contain nucleotide 5'-[alpha-thio]triphosphates in one strand of arestriction site (Walker, G. T., et al., Proc. Natl. Acad, Sci. (U.S.A.)1992, 89:392-396, incorporated herein by reference in its entirety), mayalso be useful in the amplification of nucleic acids in the presentinvention.

Strand Displacement Amplification (SDA) is another method of carryingout isothermal amplification of nucleic acids which involves multiplerounds of strand displacement and synthesis, i.e. nick translation. Asimilar method, called Repair Chain Reaction (RCR) is another method ofamplification which may be useful in the present invention and whichinvolves annealing several probes throughout a region targeted foramplification, followed by a repair reaction in which only two of thefour bases are present. The other two bases can be added as biotinylatedderivatives for easy detection. A similar approach is used in SDA.

Sulfonylurea receptor specific nucleic acids can also be detected usinga cyclic probe reaction (CPR). In CPR, a probe having a 3' and 5'sequences of non-sulfonylurea receptor specific DNA and middle sequenceof sulfonylurea receptor specific RNA is hybridized to DNA which ispresent in a sample. Upon hybridization, the reaction is treated withRNaseH, and the products of the probe identified as distinctiveproducts, generate a signal which is released after digestion. Theoriginal template is annealed to another cycling probe and the reactionis repeated. Thus, CPR involves amplifying a signal generated byhybridization of a probe to a sulfonylurea receptor specific expressednucleic acid.

Still other amplification methods described in GB Application No. 2 202328, and in PCT Application No. PCT/US89/01025, each of which isincorporated by reference in its entirety, may be used in accordancewith the present invention. In the former application, "modified"primers are used in a PCR like, template and enzyme dependent synthesis.The primers may be modified by labelling with a capture moiety (e.g.,biotin) and/or a detector moiety (e.g., enzyme). In the latterapplication, an excess of labelled probes are added to a sample. In thepresence of the target sequence, the probe binds and is cleavedcatalytically. After cleavage, the target sequence is released intact tobe bound by excess probe. Cleavage of the labelled probe signals thepresence of the target sequence.

Other nucleic acid amplification procedures include transcription-basedamplification systems (TAS) (Kwoh D., et al., Proc. Natl. Acad. Sci.(U.S.A.) 1989, 86:1173, Gingeras T. R., et al., PCT Application WO88/10315, each of which is incorporated herein by reference in itsentirety), including nucleic acid sequence based amplification (NASBA)and 3SR. In NASBA, the nucleic acids can be prepared for amplificationby standard phenol/chloroform extraction, heat denaturation of aclinical sample, treatment with lysis buffer and minispin columns forisolation of DNA and RNA or guanidinium chloride extraction of RNA.These amplification techniques involve annealing a primer which hassulfonylurea receptor specific sequences. Following polymerization,DNA/RNA hybrids are digested with RNase H while double stranded DNAmolecules are heat denatured again. In either case the single strandedDNA is made fully double stranded by addition of second sulfonylureareceptor specific primer, followed by polymerization. The doublestranded DNA molecules are then multiply transcribed by a polymerasesuch as T7 or SP6. In an isothermal cyclic reaction, the RNAs arereverse transcribed into double stranded DNA, and transcribed onceagainst with a polymerase such as T7 or SP6. The resulting products,whether truncated or complete, indicate sulfonylurea receptor specificsequences.

Davey, C., et al., European Patent Application Publication No. 329,822,incorporated herein by reference in its entirety, disclose a nucleicacid amplification process involving cyclically synthesizingsingle-stranded RNA ("ssRNA"), ssDNA, and double-stranded DNA ("dsDNA")which may be used in accordance with the present invention. The ssRNA isa first template for a first primer oligonucleotide, which is elongatedby reverse transcriptase (RNA-dependent DNA polymerase). The RNA is thenremoved from resulting DNA:RNA duplex by the action of ribonuclease H(RNase H, an RNase specific for RNA in a duplex with either DNA or RNA).The resultant ssDNA is a second template for a second primer, which alsoincludes the sequences of an RNA polymerase promoter (exemplified by T7RNA polymerase) 5' to its homology to its template. This primer is thenextended by DNA polymerase (exemplified by the large "Klenow" fragmentof E. coli DNA polymerase I), resulting as a double-stranded DNA("dsDNA") molecule, having a sequence identical to that of the originalRNA between the primers and having additionally, at one end, a promotersequence. This promoter sequence can be used by the appropriate RNApolymerase to make many RNA copies of the DNA. These copies can thenre-enter the cycle leading to very swift amplification. With properchoice of enzymes, this amplification can be done isothermally withoutaddition of enzymes at each cycle. Because of the cyclical nature ofthis process, the starting sequence can be chosen to be in the form ofeither DNA or RNA.

Miller, H. I., et al., PCT application WO 89/06700, incorporated hereinby reference in its entirety, disclose a nucleic acid sequenceamplification scheme based on the hybridization of a promoter/primersequence to a target single-stranded DNA ("ssDNA") followed bytranscription of many RNA copies of the sequence. This scheme is notcyclic; i.e. new templates are not produced from the resultant RNAtranscripts. Other amplification methods include "race" disclosed byFrohman, M. A., In: PCR Protocols: A Guide to Methods and Applications1990, Academic Press, N.Y.) and "one-sided PCR" (Ohara, O., et al.,Proc. Natl. Acad. Sci. (U.S.A.) 1989, 86:5673-5677), all referencesherein incorporated by reference in their entirety.

Methods based on ligation of two (or more) oligonucleotides in thepresence of nucleic acid having the sequence of the resulting"di-oligonucleotide", thereby amplifying the di-oligonucleotide (Wu, D.Y. et al., Genomics 1989, 4:560, incorporated herein by reference in itsentirety), may also be used in the amplification step of the presentinvention.

Test fragment and control fragment may be amplified by any amplificationmethods known to those of skill in the art, including and not limited tothe amplification methods set forth above. For purposes of the presentinvention, amplification of sequences encoding patient and wild typesulfonylurea receptor includes amplification of a portion of a sequencesuch as and not limited to a portion of the sulfonylurea receptorsequence of SEQ ID NO: 1, such as sequence of a length of about 10nucleotides to about 1,000 nucleotides, more preferably about 10nucleotides to about 100 nucleotides, or having at least 10 nucleotidesoccurring anywhere within the SEQ ID NO: 1, where sequence differencesare known to occur within sulfonylurea receptor test fragments. Thus,for example, a portion of the sequence encoding the second nucleotidebinding fragment (NBF-2) region of sulfonylurea receptor of a patientsample and a control sample may be amplified to detect sequencedifferences between these two sequences.

Following amplification of the test fragment and control fragment,comparison between the amplification products of the test fragment andcontrol fragment is carried out. Sequence differences such as and notlimited to nucleic acid transition and restriction digest patternalterations may be detected by comparison of the test fragment with thecontrol fragment. Nucleic acid transition includes and is not limited toa G to A transition at nucleic acid position 750 of SEQ ID NO: 1.Another nucleic acid transition involves a G to A transition at nucleicacid position 27 of SEQ ID NO: 31.

These nucleic acid transitions lead to restriction fragment lengthpolymorphisms as exemplified by the altered results following MspI andNciI restriction digests set forth above. Accordingly, the restrictionfragment length polymorphisms of test fragments may be compared to therestriction fragments of control fragments.

Alternatively, the presence or absence of the amplification product maybe detected. The nucleic acids are fragmented into varying sizes ofdiscrete fragments. For example, DNA fragments may be separatedaccording to molecular weight by methods such as and not limited toelectrophoresis through an agarose gel matrix. The gels are thenanalyzed by Southern hybridization. Briefly, DNA in the gel istransferred to a hybridization substrate or matrix such as and notlimited to a nitrocellulose sheet and a nylon membrane. A labelled probeencoding a sulfonylurea mutation is applied to the matrix under selectedhybridization conditions so as to hybridize with complementary DNAlocalized on the matrix. The probe may be of a length capable of forminga stable duplex. The probe may have a size range of about 200 to about10,000 nucleotides in length, preferably about 500 nucleotides inlength, and more preferably about 2,454 nucleotides in length. Thepreferred sequence of the probe is set forth in SEQ ID NO: 30.Mismatches which permit substantial similarity to SEQ ID NO: 30, such asand not limited to sequences with similar hydrophobicity andhydrophilicity, will be known to those of skill in the art once armedwith the present disclosure. Various labels for visualization ordetection are known to those of skill in the art, such as and notlimited to fluorescent staining, ethidium bromide staining for example,avidin/biotin, radioactive labeling such as ³² P labeling, and the like.Preferably, the product, such as the PCR product, may be run on anagarose gel and visualized using a stain such as ethidium bromide. SeeSambrook et al., supra. The matrix may then be analyzed byautoradiography to locate particular fragments which hybridize to theprobe. Yet another alternative is the sequencing of the test fragmentand the control fragment to identify sequence differences. Methods ofnucleic acid sequencing are known to those of skill in the art,including and not limited to the methods of Maxam and Gilbert, Proc.Natl. Acad. Sci., USA 1977, 74, 560-564 and Sanger, Proc. Natl. Acad.Sci., USA 1977, 74, 5463-5467.

A diagnostic kit for detecting PHHI comprising in one or more containersat least one primer which is complementary to a sulfonylurea receptorsequence and a means for visualizing amplified DNA is also within thescope of the present invention. Alternatively, the kit may comprise twoprimers. In either case, the primers may be selected from the groupconsisting of SEQ ID NOS: 16-24, for example. The diagnostic kit maycomprise a pair of primers wherein one primer within said pair iscomplementary to a region of the sulfonylurea receptor gene, wherein oneof said pair of primers is selected from the group consisting of SEQ IDNO: 16-24, a probe specific to the amplified product, and a means forvisualizing amplified DNA, and optionally including one or more sizemarkers, and positive and negative controls. The diagnostic kit of thepresent invention may comprise one or more of a fluorescent dye such asethidium bromide stain, ³² P, and biotin, as a means for visualizing ordetecting amplified DNA. Optionally the kit may include one or more sizemarkers, positive and negative controls, restriction enzymes such as andnot limited to MspI and/or NciI, and/or a probe specific to theamplified product.

The following examples are illustrative but are not meant to be limitingof the invention.

EXAMPLES

Purification and Partial Characterization of the 140 kDa Receptor:

HIT cell membranes were photolabeled using a radioiodinated derivativeof the second generation hypoglycemic drug, glyburide, according to themethods of Nelson, D. A., et al., JBC, 1992, 267:14928, Aguilar-Bryan,L., et al., JBC, 1992, 267:14934, and Aguilar-Bryan, L., et al., JBC,1990, 265:8218, the disclosures of which are hereby incorporated byreference in its entirety.

Glyburide (Kramer et al. FEBS Lett. 1988 229:355-359) and an iodinatedderivative of glyburide (Aguilar-Bryan et al. J. Biol. Chem. 1990265:8218-8224) are known to photolabel a 140 kDa polypeptide. Thepharmacological characteristics of the photolabeling, a kD in the lownanomolar range, and appropriate rank order of displacement with otherinsulin-releasing sulfonylureas, are those expected from studies onglyburide-induced insulin release from islets (Panten et al. Biochem.Pharm. 1989 38:1217-1229) and β-cell lines (Schmid-Antomarchi et al. J.Biol. Chem. 1987 262:15840-15844) and inhibition of K_(ATP) channelactivity. Glyburide was purchased from Sigma (St. Louis, Mo.) andprepared in stock solutions of 10 mM in dimethyl sulfoxide. Radioligandstocks were prepared by diluting high pressure liquidchromatography-purified 5-[¹²⁵ ]iodo-2-hydroxyglyburide in dimethylsulfoxide. Specific activity (cpm/mol) was measured on radioliganddiluted 1/1000 into 10 mM Tris, 100 mM NaCl, 2 mM EDTA, pH 7.4, and theabsorbance determined at 2.5 nm intervals in a UV-VIS Gilfordspectrophotometer. Dimethylsulfoxide was diluted 1/1000 into the samebuffer, and the absorbance of the buffer without drug was subtracted ateach wavelength to generate the final absorbance profile.

HIT cells, passage 67-73, were seeded in roller bottles at 50×10⁶cells/bottle in 100 ml of Dulbecco's modified Eagle's medium plus 10%fetal bovine serum. Cells were fed with 200 ml of medium plus serum 4-5times over a period of 2 weeks until the cells were confluent. Afterplating and each feeding, bottles were gassed with 5% CO₂ prior tocapping.

The cells in confluent roller bottles were washed withphosphate-buffered saline (0.14 M NaCl, 3 mM KCl, 2 mM KH₂ PO₄, 1 mM Na₂HPO₄, pH 6.8) and then incubated at room temperature with 25 ml ofphosphate-buffered saline plus 2 mM EDTA until cells detached from thesides of the bottles. Cells were pelleted at 900 xg for 10 minutes at 4°C.

All steps were carried out at 0-4° C. Cell pellets were resuspended in 5mM Tris, 2 mM EDTA, 0.1 mM PMSF, pH 7.4, using approximately 5 ml ofbuffer for each roller bottle. Cells were placed on ice for 40 minutesto allow swelling and then homogenized with 10 strokes of a motorizedglass-Teflon homogenizer (500 rpm). The homogenate was centrifuged at1000 xg for 10 minutes to remove nuclei and cellular debris, and thesupernatant transferred to 30 ml of Beckman polycarbonate, screw-capultracentrifuge tubes. Supernatants were centrifuged at 100,000 xg for60 minutes in a Beckman 60 Ti rotor. The pellets were resuspended inmembrane storage buffer (10 mM Tris, 100 mM NaCl, 2 mM EDTA, 20%glycerol, 0.1 mM PMSF, pH 7.4). 200 mg of membrane protein weretypically obtained from 20 roller bottles.

Membranes were stored at -80° C. at 5 mg/ml protein in 10 mM Tris (pH7.5), 0.1 M NaCl, 2 mM EDTA, 20% glycerol. To monitor receptorpurification, an aliquot (5-20 ml) of the membranes was incubated with 1nM [¹²⁵ I]-iodo-2-hydroxyglyburide for 15 minutes and the samplephotolabeled. Binding of 5-[¹²⁵ I]-iodo-2-hydroxyglyburide (5-10 nM) tomembranes was done for 30 minutes at 23° C. Aliquots were pipetted ontoparafilm and irradiated at 23° C. in a UV cross-linker (FisherScientific). The energy settings for the UV cross-linker were factorycalibrated at 254 nm. For cross-linking at 312 nm, a conversion factorwas estimated by determining the time required for the UV cross-linkerto deliver a specific amount of energy with each set of bulbs, and thenmultiplying by the ratio of these times.

All subsequent steps were performed at room temperature in the presenceof 0.1 mM PMSF, 0.1 mM phenanthroline and 0.1 mM iodoacetamide. 20%(w/v) digitonin was freshly prepared by boiling in deionized water, thenadded to 200-400 mg thawed labeled membranes to a final concentration of1%. Membranes were solubilized for 15 minutes then sedimented for 1 hrat 100,000 xg. The supernatant was divided into 4 ml aliquots and eachaliquot was chromatographed over a 1 ml Concanavalin A-Sepharose columnequilibrated with 25 mM Tris-HCl, pH 7.5,0.1 M NaCl, 2 mM EDTA, 1%digitonin. The solution was cycled through the column twice beforewashing the column with 8 ml of the equilibration buffer. Retainedprotein was eluted with 4 ml of the same buffer containing 0.5 M methylα-D-mannopyranoside. The eluted protein was stored at -80° C. Three ConA eluates were combined, then cycled twice over a 1 ml column ofreactive green 19-agarose equilibrated with 50 mM HEPES (pH 8.5), 2 mMEDTA, 0.2% digitonin. The column was washed with 8 ml of theequilibration buffer followed by 8 ml of the same buffer containing 0.4M NaCl. The retained protein was eluted with 4 ml of the equilibrationbuffer containing 1.5 M NaCl. The two pooled eluates were diluted 1:1with the HEPES equilibration buffer without NaCl and cycled twice over a1 ml phenylboronate-10 agarose column. The column was washed with 8 mlof the HEPES buffer, followed by 2 ml of 0.1 M Tris-HCl, pH 7.5, 2 mMEDTA, 0.1% digitonin. Protein was eluted with 4 ml of 0.1 M Tris (pH7.5), 2 mM EDTA, 0.1% SDS. The protein was concentrated to 0.5 ml usinga 100,000 MW cutoff Amicon filter, pretreated with 5% Tween-20, thenloaded onto a single 5 cm wide lane of a 5.5% polyacrylamide SDS gel.After electrophoresis the gel was stained with Coomassie blue,destained, and the receptor band excised with a razor blade. Thereceptor was electroeluted into a 14,000 MW cutoff dialysis bag andconcentrated by Amicon filtration.

Table 1 summarizes the yields and fold-purification in the schemedeveloped for receptor purification. The amount of receptor, yields, andfold-purification reported after each step are based on theradioactivity, determined by γ counting, in the 140 kDa band afterelectrophoresis relative to the total protein loaded on a gel lane (asdetermined using the BioRad protein assay). HIT cell membranes containapproximately 1.6 pmol of receptor per mg of membrane protein asdetermined by filtration binding (Aguilar-Bryan et al. J. Biol. Chem.1990 265:8218-8224).

                                      TABLE 1                                     __________________________________________________________________________    Purification of the High Affinity 140 kDa Sulfonylurea Receptor from HIT      cells                                                                               Total Volume                                                                         Total Protein                                                                       Receptor                                                                           Receptor                                                                           Purification                                                                        Yield                                        Step ml mg pmol pmol/mg ˜fold %                                       __________________________________________________________________________    Crude 90     200   320  1.6  1     100                                          Membranes                                                                     Supernatant 90 150 240  1.6 1 75                                              ConA- 48 10.2 80 7.8 4.9 25                                                   Sepharose                                                                     Reactive 16 1.8 56 31.1 19.5 18                                               Green                                                                         19-agarose                                                                    Phenyl 4 0.56 45 80.4 50.4 14                                                 boronate                                                                      agarose                                                                       SDS-PAGE 0.2 ˜0.002  8 4000 2507 2.5                                    electroelute                                                                __________________________________________________________________________

For the autoradiogram depicted in FIG. 1, 1-2 μg of purified,radiolabeled receptor was made 1% in β-octylglucoside and divided into 6aliquots. Lane 1 contained receptor kept on ice. The receptor wasincubated in the presence (lane 2) and absence (lane 3) of Endo F for 30min at 37° C. Aliquots of the samples for lanes 1-3 were furtherincubated with V8 protease (1 μg/10 μl) for 30 min at 37° C., yieldingtwo radiolabeled peptides of 66 and 49 kDa (lanes 4 and 6), both ofwhich are N-glycosylated as indicated by the mobility shift after endo Ftreatment (lane 5). To obtain N-terminal sequence from the intactreceptor, 2 μg of protein was separated by electrophoresis on a single,0.8 cm wide lane of a 5.5% gel. The receptor was transferred to ProBlot(Applied Biosystems) in 10 mM CAPS (pH 11), 10% MeOH, the filter stainedfor 10-20 seconds with Coomassie blue, destained, the band excised andmicrosequenced. To prepare receptor fragments for microsequencing, 10 μgof purified receptor was cleaved with V8, electrophoresed on a singlelane and the fragments from the partial digest transferred to ProBlot.Fragments were prepared and sequenced multiple times as indicated in thefigure. Gels used in the preparation of receptor and fragments formicrosequencing were aged overnight, and the top tray buffer contained0.1 mM thioglycolate.

The purified receptor showed a small apparent molecular weight decrease(ΔM_(r) ˜3000) following treatment with Endoglycosidase F/N-glycosidaseF (Endo F) and yielded two bands following limited cleavage with V8protease (FIG. 1). Each of the major labeled proteolytic fragments,M_(r) ˜69 and 49 kDa, shift mobility after digestion with Endo F.Identical N-terminal sequence, 15-25 residues, were recovered from eachof the major labeled peptides. No residue was obtained at residue 9 whenthe glycosylated peptides were sequenced; an aspartic acid wasidentified at residue 9 in the deglycosylated receptor indicating thisis an N-glycosylated asparagine. In addition, N-terminal sequences wererecovered on two unlabeled V8 peptides and a third minor labeledpeptide. The results indicate there is an N-linked glycosyl group atresidue nine in the mature receptor, suggesting that the N terminus isextracellular, and that the sulfonylurea labeling site is within thefirst 50 kDa of the receptor.

Two multiple antipeptide antibodies (MAPs), directed against residues 1through 8 and 10 through 20 both immunoprecipitate photolabeled 140 kDareceptors from HIT, mouse αTC-6, and rat insulinoma (RIN) cells. MAPswere prepared by synthetic protein sequencing (Perkin Elmer-ABI, 430 APeptide Synthesizer, Foster City, Calif.) to obtain antibodies toM-P-L-A-F-C-G-T, SEQ ID NO: 10, residues 1-8 of SEQ ID NOS: 28 and 29.This process was repeated for residues 10-20 of SEQ ID NOS: 28 and 29,N-H-S-A-A-Y-R-V-D-Q-G, SEQ ID NO: 11. A purified sulfonylurea receptorprotein was immunoprecipitated from HIT cells using the MAPs prepared asset forth above.

HIT cell membranes were incubated with 5-[¹²⁵ I]iodo-2-hydroxyglyburide,photolabeled, solubilized with 1% digitonin, centrifuged at 100,000 xgand the supernatant incubated with 1/10 volume of preimmune serum,immune serum, immune serum+anti-MAP 10-20, or immune serum+irrelevantMAP peptide. 50 μl of protein A-Sepharose was added and the mixture wasincubated for 2 hours at room temperature, the beads washed with buffer,heated in the presence of pH 9 sample buffer, eletrophoresed on a 6%polyacrylamide SDS gel, and an autoradiogram prepared.

The immunoprecipitation was competed using the immunizing peptide, butnot the other MAPS (FIG. 2). The amino acid sequence is derived from thephotolabeled protein and the N-terminal amino acid sequence is conservedbetween mouse, rat, and hamster.

Isolation and Characterization of cDNA Clones:

Degenerate PCR primers with flanking restriction sites were designedbased on the sequence obtained from the labeled peptides. The primersused were as follows:

primer 1 (SEQ ID NO: 23):

5' GAGAGAAGCTT(T/C)TG(T/C)GG(T/C/G/A)GA(A/G)AA(T/C)CA-3'

primer 2 (SEQ ID NO: 24):

5' GAGAGAGAATTCC(T/C)TG(A/G)TC(T/C/G/A)AC(T/C/G/A)C(G/T)(A/G)TA-3'

The bases in parenthesis indicate the degeneracy at that position. Thesequence in bold was derived from the peptide sequence obtained from theN-terminus of the sulfonylurea receptor. The remaining 5' sequence wasadded to facilitate subcloning. Primer 1 has a HindIII site at the 5'end; Primer 2 was engineered with an EcoRI site at the 5' end. Theseprimers were used in a standard PCR reaction with a random primed cDNAlibrary, constructed in λZAPII using mouse α-cell poly A+ mRNA, astemplate. The following cycle times and temperatures were employed: 94°C. for 10 minutes; 85° C. for 3 minutes, [50° C. for 2 minutes, 72° C.for 5 minutes, 94° C. for 2 minutes,] 50° C. for 2 minutes, 72° C. for 5minutes.

The bracketed conditions were cycled 30 times. From the N-terminalpeptide sequence of the receptor a 47 base pair coding region wasexpected to be amplified plus the 20 base pairs added to the primers tofacilitate cloning yielding an expected 67 base pair product. The 47base pair coding region was predicted to have 14 base pairs that werenot present in the primers. The PCR product obtained was approximately67 base pairs and was restricted with EcoRI and HindIII, subcloned intoM13 and sequenced. The resulting sequence gave the expected 14 basepairs indicating the sequence was derived from the receptor. The 47 basepair oligonucleotide given below was synthesized based on the consensussequence derived from nine M13 clones:

5' TTTTGCGGGACGGAGAATCACTCGGCCGCCTACCGCGTCGACCAAGG-3'

(SEQ ID NO: 25). This oligonucleotide was used to screen the randomprimed mouse αTC-cell cDNA library.

A 1.1 kb cDNA was cloned which encoded 28 amino acids obtained frompeptide sequencing. This cDNA fragment was used to screen RIN and HITcell cDNA λ libraries to obtain full sequence.

The nucleotide sequence of a 4635 bp rat receptor cDNA incluldes an openreading frame that encodes a 1498 amino acid protein with a mass of167,834 daltons, larger that predicted by SDS polyacrylamide gelelectrophoresis. Aguilar-Bryan, L., et al., JBC, 1990, 265:8218. Thereis a single insertion of an asparagine at position 742 and a deletion ofa threonine at position 831. The first difference between the hamsterand rat sequences is in the same relative position, 21 residuesC-terminal of the Walker consensus site, as the ΔF508 deletion seen in acommon cystic fibrosis transconductance regulator (CFTR) mutation(Riordan et al. Science 1989 245:1066-1073). In addition to theinsertion and deletion, the first nucleotide binding fold containsapproximately a third (10/33) of all differences between the twospecies.

The mature rat protein, defined by peptide sequencing, begins with aproline following the methionine start site. In the RIN cell receptorsthe adjacent amino acid is a methionine. This is the initiatingmethionine based on the surrounding sequence which is a good fit to theconsensus pattern for initiation, GCC(A/G)CCAUG(G) (SEQ ID NO: 26)(Kozak, M. Cell 1986 44:283), including the strongly conserved A atposition -3. However, in the mouse receptor, an additional 35 aminoacids is found preceding this proline which cannot eliminate thepossibility that some forms of the hamster and rat receptors havesimilar leader sequences. Confirming the chemical sequence, residue 9 inthe mature proteins is an asparagine within a consensus glycosylationsite.

A Blast search of the National Center for Biotechnology Information(NCBI) nucleotide database with the receptor sequence produced matcheswith several members of the P-glycoprotein/multidrug resistance proteinfamily. A similar search with the amino acid sequence indicated thesulfonylurea receptor is a member of the ATP-binding cassettesuperfamily with two putative nucleotide binding domains. Thesulfonylurea receptor sequence revealed 29% similarity, to anATP-binding cassette superfamily member, termed a multidrugresistance-associated protein (MRP), isolated from a small cell lungcarcinoma cell line (H69AR) selected with doxorubicin (Cole et al.Science 1992 258:1650-1654). A cluster analysis of this molecule, dvhuarin the Protein Identification Resource (PIR) database, indicates it isrelated to the leishmania P-glycoprotein-related molecule (Lei/PgpA),the CFTRs (human (Hum/CFTR), bovine (Bov/CFTR), mouse (Mus/CFTR), anddogfish (Squ/CFTR)) (Cole et al. Science 1992 258:1650-1654). A similarresult was obtained for the sulfonylurea receptor with the additionalinclusion of the Xenopus CFTR indicating the receptor is a member ofthis cluster.

The identification of the nucleotide binding domains goes beyond simplyhaving Walker "A" and "B" consensus sequences. The receptor is similarto the 230-240 amino acid nucleotide binding domain(s) described by(Hyde et al. Nature 1990 346:362-365) and database searches findsimilarities to the nucleotide binding fold of ATP-binding proteins. Themore conserved of the two receptor nucleotide binding folds, based onsimilarity with other ATP-binding proteins and the comparison of the ratand hamster sequences, is at the C-terminal end.

RNA Analysis:

Northern blot analysis of poly A+ mRNA isolated from RIN, HIT and αTC-6cells, previously shown to have the high affinity receptor by drugbinding and photolabeling studies (Aguilar-Bryan et al J. Cell. Biochem.Suppl. 1994 18A:133) each have an approximately 5000 nucleotidetranscript, see FIG. 3. A preliminary tissue distribution study showsthe same size transcript is present in mouse brain and heart.

Predicted Protein Structure:

Sequence similarities indicate the sulfonylurea receptor has twopotential ATP binding folds. The size and additional sequencesimilarities with P-glycoproteins and CFTRs suggest the receptor has asimilar structure. Hydrophobicity (FIG. 4) and hydrophobicity versushydrophobic moment (Eisenberg et al. J. Mol. Biol. 1984 179:125) plotswere used to generate a model for the receptor (FIG. 5). Two constraintswere imposed on the model structure: the glycosylation site is on theexternal face of the membrane and both nucleotide binding domains are onthe internal face. The `classical` ATP-binding cassette superfamilymodel proposes duplication of a unit consisting of six transmembranespanning helices followed by a nucleotide binding domain. Thesulfonylurea receptor differs from this model and has at least ninepotential transmembrane helices before the first nucleotide bindingdomain but only four between the two nucleotide binding domains (FIG.5). The multidrug resistance-associated protein (MRP) is predicted tohave 8 transmembrane spanning helices (Cole et al. Science 1992258:1650-1654).

Phosphorylation has been implicated in regulation of K_(ATP) channelactivity (Schwanstecher et al. J. Pharmacol. Exper. Ther. 1992262:495-502) and has been proposed to change the affinity of thesulfonylurea receptor for various ligands. There are 21 potentialphosphorylation sites in the receptor sequence; 3 protein Kinase A (pKA)sites and 18 protein kinase C (pKC) sites. The pKA site at 278 ispredicted to be on the external face of the membrane, while those atpositions 1363 and 1417 are in the second nucleotide binding fold. Fourof the pKC sites (positions 151, 200, 304 and 1213) are predicted to beextracellular or in a membrane spanning helix. Seven of the remaining 14are in the nucleotide binding folds (NBF); 4 in NBF-1, and 3 in NBF-2.One of the latter sites, Thr 1297 in the Walker A consensus site, isexpected to alter nucleotide binding if it is accessible forphosphorylation.

Functional Properties, In Vitro Translations:

mRNA, transcribed by SP6 RNA polymerase from the rat cDNA subcloned intopGEM4, was translated in vitro. Approximately 0.5 μg of mRNA was heatedto 70° C. for 10 minutes, immediately cooled on ice then added to rabbitreticulocyte lysate (Promega, Madison, Wis.) supplemented withribonuclease inhibitor, an amino acid mixture, and [³⁵ S]methionine. Thereaction mixture was incubated at 30° C. for 60 minutes then aliquotswere subject to electrophoresis on SDS polyacrylamide gels usingstandard protocols. The gels were dried and autoradiographed.

The resulting protein was approximately 137 kDa, indicating the receptorbehaves anonymously on SDS polyacrylamide gels having a faster thanexpected mobility, see FIG. 6A. A similar anomalous behavior has beenreported for CFTRs (Gregory et al. Nature 1990 347:382-386).

Anti-Nucleotide Fold Antibodies Immunoprecipitate the Photolabeled 140kDa Receptor:

Antibodies were produced against two fusion proteins containing the twonucleotide binding folds. Fragments of the receptor cDNA were subclonedin frame into pMALc (New England BioLabs, Boston, Mass.) at theC-terminal end of the DNA encoding the maltose binding protein (MBP). Aplasmid expressing the first nucleotide binding fold fused to MBP wasconstructed by restricting pMALc with StuI and SalI and restricting thesulfonylurea receptor cDNA with PvuII plus XhoI. A unique 500 base pairfragment was gel purified from the receptor cDNA digest and subclonedinto pMALc. The construction was verified by sequencing. The receptorsegment expressed is leu708 to leu874. Expression was obtained in E.coli following transformation and induction by isopropylthiogalactosideper the manufacturer's directions. The expressed proteins were found tobe in inclusion bodies which were solubilized in SDS and separated onSDS polyacrylamide gels, see FIG. 6B. The fusion protein waselectroeluted, concentrated, and used as an immunogen. The solubilizedprotein in 200 μg amounts, with complete, or incomplete Freund'sadjuvant, was injected interdermally into rabbits using a standard 2-3week regimen of bleeding and boosting.

Injection of Xenopus Oocytes with Receptor mRNA:

mRNA, approximately 50 ng, transcribed as described above, was injectedinto Xenopus oocytes. The injected oocytes were assayed for K+ channelactivity after 1-5 days using both two-electrode and patch clampmethods. New K+ currents in the injected oocytes were not detected.Similarly, co-injection of mRNAs transcribed from cDNAs encoding twosmall inward rectifiers, ROMK1 (Ho et al. Nature 1993 362:31-38) or abrain homolog of IRK1 (Kelly et al. Biophysical J. 1994 66(2):A109)failed to confer sulfonylurea sensitivity on these K+ channels. Theresults suggest that the 140 kDa receptor does not have intrinsic K+channel activity, or that Xenopus oocytes are not an adequate backgroundfor their expression.

Transfection Experiments:

The sulfonylurea receptor cDNA has been ligated into eukaryoticexpression vectors containing SV40 virus, adenovirus and cytomegalovirus(CMV) promoters. These plasmids have been transfected into COS cellswhich do not have the high affinity sulfonylurea receptor as determinedby filtration binding and photolabeling studies. To date experimentswith the SV40 plasmid have shown that the transfected cells produce anmRNA of the appropriate size as determined by Northern blots withreceptor cDNA. Metabolic labeling experiments with the SV40 plasmidwhere transfected and non-transfected cells were labeled with [³⁵ S]methionine indicate that the transfected, but not the non-transfectedcells, synthesize an appropriate sized protein which can beimmunoprecipitated with the antinucleotide binding fold antibodies. Thelevel of receptor synthesized by COS cells using this promoter has beenlow using SEQ ID NOS: 27 and 28. Expression levels are high using SEQ IDNOS: 4, 5, 7, and 8 from rat and hamster.

Chromosomal localization of the Sulfonylurea Receptor Gene

Chromosomal localization of the Sulfonylurea Receptor (SUR) gene tonormal male human banded chromosomes was determined by utilization ofthe fluorescence in situ hybridization (FISH) technique by staining with4,6-diamidino-2-phenylindole (DAPI). A metaphase spread showed the twochromosome 11 homologues which map the SUR cDNA to 11p15.1. Overlappinghuman SUR cDNA plasmids "mid" and "3", totaling 3.8 kb, were labeledwith biotin-14-dATP (GIBCO) and hybridized in situ to standard metaphasespreads from normal male peripheral blood lymphocytes, according to themethods of P. Lichter et al., Science 247, 64 (1990), the disclosure ofwhich is hereby incorporated by reference in its entirety. Thebiotin-labeled DNA was detected using Fluorescein-Avidin DCS (VectorLaboratories, Burlingame, Calif.). Chromosomes were identified bysimultaneous DAPI staining, which produces a Q-banding pattern. Fifteenmetaphases were analyzed. Digital images were obtained with a cooledcharge-coupled device camera mounted on a standard epifluorescentmicroscope (Axioplan; Zeiss, Thronwood, N.Y.). Images were acquiredusing the software ISee (Inovision Co.) running on a Sun workstation.Fluorescein isothiocyanate and DAPI fluorescence were recordedseparately as gray scale images and then merged using the softwarepackage NIH 1.55 (J. W. Ijdo, E. A. Lindsay, R. A. Wells, A. Baldini,Genomics 14, 1019 (1992)). Eighty-five per cent of metaphases analyzedshowed specific hybridization signal on both chromatids of the twochromosomes 11 at 11p15.1.

Partial cDNA clones, comprising 3.8 kb of coding sequence of the humanhomologue of SUR, were obtained from a human pancreatic cDNA library(provided by Graeme Bell, University of Chicago, and commerciallibraries of Clontech, Palo Alto, Calif. and Invitrogen, San Diego,Calif.). The library was produced in lambda gt10 phage (Bell RINlibrary) and screened with a 2294 bp hamster cDNA probe encoded by SEQID NO: 30.

The protocol for making the library is provided by Sambrook et al.,supra. Poly A+ mRNA was isolated using an oligo dT column. Poly A+ mRNAwas incubated with oligo dT and random hexamers plus reversetranscriptase (such as MMLV RT from Promega, Stratagene or NEBL) anddNTPs to produce single strand cDNA. The single strand cDNA is treatedwith E. coli DNA polymerase, RNAseH and dNTPs, then ligated to linkersthat have EcoRI sites to produce double stranded DNA. The final productis restricted with EcoRI and ligated, using T4 DNA ligase, into lambdaphage DNA that has been similarly restricted and dephosphorylated withalkaline phosphatase to prevent self ligation. The ligated product ispackaged into phage using commercially available packaging extracts.

Screening involved plating and hybridizing at 55° C. or 65° C. in 5× or6× SSC (according to the methods of Sambrook, et al.). 55° C. was usedfor cross species screens and 65° C. was employed for the same species.Two washes were carried out at room temperature using 2× SSC, then oneat the hybridization temperature of 65° C using 0.1× SSC.

Hybridizations and washes were done at reduced stringency (55° C.) usingmethods according to F. M. Ausubel et al., Current Protocols inMolecular Biology (Greene Publishing Associates, Inc, New York, N.Y.,1989), Chap. 6, the disclosures of which are hereby incorporated byreference in their entirety. Subsequent screening was done at higherstringency (65° C.), using a human cDNA of SEQ ID NO: 31 obtained fromthe first screen as a probe.

Characterization of these cDNA clones by sequence analysis revealed anoverall homology of 95% with the rat SUR gene. A specific hybridizationsignal was detected at the band 11p15.1 in 85% of metaphases on bothchromatids of the two chromosomes 11.

Detection of Sulfonylurea Receptor Mutations in PHHI AffectedIndividuals

Mutational analysis was performed on samples from 16 affected progeny ofnine consanguineous matings. In each case, diagnosis of PHHI was basedon criteria established by A. Aynsley-Green et al., supra., thedisclosure of which is hereby incorporated by reference in its entirety.The parents in six families were first cousins, in two families secondcousins, and in one family more distantly related. Eight families wereof Saudi Arabian origin, recruited from the patient population of theArabian American Oil Company Hospital Medical Services Organization,after institutional approval was received, and one was of Germanicorigin. Family labels follow the form of Thomas et al., supra.

Studies indicated that no major insertions or deletions of the SUR locushad occurred in three of the families. The first region evaluated, bydirect sequence analysis, was the second nucleotide binding fold (NBF-2)of the human SUR homologue (FIG. 7). This is the most highly conservedregion of the SUR gene, and in other superfamily members it, as well asNBF-1, has functional importance for control of channel activity throughinteraction with cytosolic nucleotides. S. C. Hyde, Nature 346, 362(1990) and M. J. Weish, A. E. Smith, Cell 73, 1251 (1993).

To obtain this genomic structure, a normal human lymphocyte genomicbacteriophage library (provided by Mary Beth Humphrey, Baylor College ofMedicine) was screened, using standard methods according to F. M.Ausubel et al., supra., with a human partial SUR cDNA probe of SEQ IDNO: 31 (cDNA probe, "3prime").

The human genomic library was made in lambda FIX using materialssupplied by Stratagene, Inc. Briefly, genomic DNA was partially digestedwith Sau3A, the fragments were precipitated with ethanol, resuspendedwith precut lambda FIX DNA which has compatible ends, ligated with T4DNA ligase and packaged and screened.

Hybridizations and washes were done at reduced stringency (55° C.) usingmethods according to F. M. Ausubel et al., Current Protocols inMolecular Biology (Greene Publishing Associates, Inc, New York, N.Y.,1989), Chap. 6, the disclosures of which are hereby incorporated byreference in their entirety. The library was screened with a 1.2 kbhamster cDNA probe of SEQ ID NO: 32, which spans the SUR NBF2 sequence.Subsequent screening was done at higher stringency (65° C.), using ahuman cDNA.

Screening involved plating and hybridizing at 55° C or 65° C. in 5× or6× SSC (according to the methods of Sambrook, et al.). 55° C. was usedfor cross species screens and 65° C. was employed for the same species.Two washes were carried out at room temperature using 2× SSC, then oneat the hybridization temperature of 65° C. using 0.1X× SSC.

Inserts in the bacteriophage clone λG4 were subcloned into pBluescript11 (Stratagene, La Jolla, Calif.). Plasmids were purified using standardcesium chloride purified methods, restricted using the appropriatedesired enzyme(s). The fragments were purified by electrophoresis on lowmelt agarose and cut out of the gel. A 1-to-5 microliter aliquot of thedesired fragment and 1 microgram of the appropriately restricted plasmidcarrying a selectable ampicillin resistance marker (such as pBluescriptfrom Stratagene, Inc.) were melted at 65° C., mixed and diluted to 20microliters with a buffer containing T4 DNA ligase and ATP, thenincubated for 4-18 hours before transforming into E. coli and selectingon ampicillin plates.

Exon-intron boundaries were defined by comparing the nucleotidesequences of the human SUR gene and cDNA, which were obtained using thedideoxy chain termination method (Sequenase; U.S. Biochemicals,Cleveland, Ohio).

Because of the consanguineous matings and autosomal recessiveinheritance pattern of this disorder, affected individuals are expectedto be homozygous by descent at the disease gene locus. E. S. Lander andD. Botstein, Science 236, 1567 (1987), the disclosure of which is herebyincorporated by reference in its entirety. Direct sequencing of apancreatic cDNA product, isolated from an affected child of Family 6,revealed a 109 bp deletion within the NBF-2 region which corresponded toskipping of an exon resulting in a cDNA product of about 2190 bp inlength using primers of SEQ ID NOS: 20 and 21 as compared to mRNA ofabout 2080 bp in length. The effects of this skipping event are severeand include production of a frameshift, premature truncation of theprotein due to inclusion of a stop 24 codons later, and disruption ofthe NBF-2 (FIGS. 8A and 8B). The splice sites of the skipped exon wereevaluated at the genomic DNA level and a homozygous G to A pointmutation, located within the 5' splice site at the last base of theskipped exon, was found (FIG. 8C). A recognition site for therestriction endonuclease MspI is destroyed by this base change,providing a means to confirm and test for the presence of the mutation.mRNA was directly isolated using Oligotex (Qiagen Inc., Studio City,Calif.) from a fresh-frozen pancreatic tissue sample and reversetranscribed (RT), using random primers (Invitrogen, San Diego, Calif.),with Superscript 11 (GIBCO-BRL) into cDNA. For cloning of the NBF-2region, an initial PCR amplification with SEQ ID NOS: 23 (primer 22(located 5' of 17)) and 19 (primer 29) was followed by a secondamplification of a portion of the reaction with SEQ ID OS: 16 (primer17) and 19 (primer 29) using conditions described by P. M. Thomas, G. J.Cote, D. M. Hallman, P. M. Mathew, Am. J. Hum. Genet., in press, supra.

PCR products were amplified using hybridization at 60° C. for 1 minute,elongated at 72° C. for 1 minute and denatured at 93° C. for 1 minutefor thirty cycles. Hybridization may be carried out at temperatures ofbetween about 55° C. to about 65° C. The amplified product was clonedinto pCR 11™ vector (Invitrogen, San Diego, Calif.) and sequenced, asabove. pCR 11™ vector is set forth in FIG. 10. For detection of themutation in genomic fragments, 100 ng of genomic DNA was amplified usingSEQ ID NOS: 14 and 16, primers 28 and 29B, as above except in thepresence of PCR buffer N (Invitrogen, San Diego, Calif.), and eitherdirectly PCR sequenced according to the methods of S. Khorana, R. F.Gagel, G. J. Cote, Nucleic Acids Res. 22, 3425 (1994), the disclosure ofwhich is hereby incorporated herein by reference in its entirety, or cutwith 5 U of Mspl (GIBCO-BRL) at 37° C. for 2 hours and run on a 10%polyacrylamide gel. Visualization of products was by silver staining.Both affected children of Family 6 were homozygous, while the parentsand two unaffected siblings were found to be heterozygous, for themutation (FIG. 8D). Preliminary semiquantitative analysis revealedmarkedly decreased expression of the mutant SUR message upon comparisonof patient and age-matched normal control pancreatic samples, suggestinginstability of the mutant message.

Thirteen additional affected children, from six families of SaudiArabian origin and one family of German origin, were found to behomozygous for this mutation, as demonstrated by loss of the Msplrestriction enzyme recognition site. In all families, homozygous loss ofthe Mspl site cosegregated with disease phenotype, and in Families 1-3and 5 genotype analysis for this mutation agreed with previouslyreported haplotype data, P. M. Thomas, G. J. Cote, D. M. Hallman, P. M.Mathew, Am. J. Hum. Genet., in press, supra. Direct sequencing ofPCR-amplified genomic DNA from a representative affected member of eachfamily determined that all exhibited the homozygous G to A mutation.

Family 4 demonstrated a unique mutation in the 3' splice site sequencepreceding the start of the NBF-2 (FIG. 9A). This G to A mutationdestroys an Ncil restriction endonuclease site and homozygous loss ofthis site cosegregated with disease phenotype within the family. Again,genotype analysis of the members of this family supported previouslyreported haplotype data, P. M. Thomas, G. J. Cote, D. M. Hallman, P. M.Mathew, Am. J. Hum. Genet., in press, supra.; both parents areheterozygotes for the mutation and the unaffected sibling is homozygousfor the wild type allele (FIG. 9B). Since a pancreatic tissue samplefrom an affected individual in Family 4 was unavailable and we wereunable to recover the SUR message from transformed lymphocytes, achimeric construct was created to examine the effects of this mutationon the RNA splicing pathways according to the methods of R. Takahashi,et al., Nature Genet. 7, 79 (1994); I. Satokata, et al., Proc, Natl.Acad. Sci. 87 9908 (1990); H. Lou, G. J. Cote, R. F. Gagel, Mol. Endo.8, 1618 (1994), the disclosure of each hereby incorporated by referencein its entirety.

Genomic DNA from affected and normal individuals was PCR-amplified usingthe SEQ ID NOS: 12 and 18 and cloned into pRSVhMT2A. Constructs weretransfected into the human glioblastoma cell line SNB 19 usingLipofectamine™ (Gibco-BRL, Gaithersburg, Md.). RT-PCR analysis wasperformed, with SEQ ID NOS:14 (primer 16) and 19 (primer DS8), asdescribed by H. Lou, G. J. Cote, R. F. Gagel, Mol. Endo. 8, 1618 (1994),the disclosure of which is incorporated herein by reference in itsentirety. The plasmids and their cDNA products were sequenced with SEQID NO: 13 (primer 34al). Genomic DNA fragments were PCR-amplified withSEQ ID NOS: 13 and 14 (primers 34al and 16) and digested with Ncil, asin FIG. 8. With the construct containing the mutation, no wild typesplicing pattern occurred. Instead, use of three cryptic 3' splice siteswas demonstrated resulting in a 7 bp addition, a 20 bp deletion, and a30 bp deletion in the exon (FIG. 9D). A similar intronic 3' spliceacceptor mutation, described in the disorder 21-hydroxylase deficiency,also resulted in lack of the wild type splicing pattern, producedseveral cryptic splice products, and abolished normal protein activity.Y. Higashi, et al., Proc. Natl. Acad. Sci., USA 85, 7486 (1988), thedisclosure of which is incorporated herein by reference in its entirety.

All PCR products prepared from genomic DNA of 100 normal, unrelatedindividuals showed normal Mspi and Ncil restriction patterns, indicatingthat neither mutation is a common polymorphism. The data presentedprovides evidence that mutations in the SUR gene cause familialpersistent hyperinsulinemic hypoglycemia of infancy.

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended claims.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                   - -  - - (1) GENERAL INFORMATION:                                             - -    (iii) NUMBER OF SEQUENCES: 49                                          - -  - - (2) INFORMATION FOR SEQ ID NO:1:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1308 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                               - - GGACCTGCAG CAGCTGGATG ACACCACCCA GCTTCCACTT CTCTCACACT TT -            #GCCGAAAC     60                                                                 - - CGTAGAAGGA CTCACCACCA TCCGGGCCTT CAGGTATGAG GCCCGGTTCC AG -            #CAGAAGCT    120                                                                 - - TCTCGAATAC ACAGACTCCA ACAACATTGC TTCCCTCTTC CTCACAGCTG CC -            #AACAGATG    180                                                                 - - GCTGGAAGTC CGAATGGAGT ACATCGGTGC ATGTGTGGTG CTCATCGCAG CG -            #GTGACCTC    240                                                                 - - CATCTCCAAC TCCCTGCACA GGGAGCTCTC TGCTGGCCTG GTGGGCCTGG GC -            #CTTACCTA    300                                                                 - - CGCCCTAATG GTCTCCAACT ACCTCAACTG GATGGTGAGG AACCTGGCAG AC -            #ATGGAGCT    360                                                                 - - CCAGCTGGGG GCTGTGAAGC GCATCCATGG GCTCCTGAAA ACCGAGGCAG AG -            #AGCTACGA    420                                                                 - - GGGACTCCTG GCACCATCGC TGATCCCAAA GAACTGGCCA GACCAAGGGA AG -            #ATCCAGAT    480                                                                 - - CCAGAACCTG AGCGTGCGCT ACGACAGCTC CCTGAAGCCG GTGCTGAAGC AC -            #GTCAATGC    540                                                                 - - CCTCATCTCC CCTGGACAGA AGATCGGGAT CTGCGGCCGC ACCGGCAGTG GG -            #AAGTCCTC    600                                                                 - - CTTCTCTCTT GCCTTCTTCC GCATGGTGGA CACGTTCGAA GGGCACATCA TC -            #ATTGATGG    660                                                                 - - CATTGACATC GCCAAACTGC CGCTGCACAC CCTGCGCTCA CGCCTCTCCA TC -            #ATCCTGCA    720                                                                 - - GGACCCCGTC CTCTTCAGCG GCACCATCCG ATTTAACCTG GACCCTGAGA GG -            #AAGTGCTC    780                                                                 - - AGATAGCACA CTGTGGGAGG CCCTGGAAAT CGCCCAGCTG AAGCTGGTGG TG -            #AAGGCACT    840                                                                 - - GCCAGGAGGC CTCGATGCCA TCATCACAGA AGGCGGGGAG AATTTCAGCC AG -            #GGACAGAG    900                                                                 - - GCAGCTGTTC TGCCTGGCCC GGGCCTTCGT GAGGAAGACC AGCATCTTCA TC -            #ATGGACGA    960                                                                 - - GGCCACGGCT TCCATTGACA TGGCCACGGA AAACATCCTC CAAAAGGTGG TG -            #ATGACAGC   1020                                                                 - - CTTCGCAGAC CGCACTGTGG TCACCATCGC GCATCGAGTG CACACCATCC TG -            #AGTGCAGA   1080                                                                 - - CCTGGTGATC GTCCTGAAGC GGGGTGCCAT CCTTGAGTTC GATAAGCCAG AG -            #AAGCTGCT   1140                                                                 - - CAGCCGGAAG GACAGCGTCT TCGCCTCCTT CGTCCGTGCA GACAAGTGAC CT -            #GCCAGAGC   1200                                                                 - - CCAAGTGCCA TCCCACATTC GGACCCTGCC CATACCCCTG CCTGGGTTTT CT -            #AACTGTAA   1260                                                                 - - ATCACTTGTA AATAAATAGA TTTGATTATT TCCTAAAAAA AAAAAAAA  - #                  1308                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:2:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1308 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 2..1186                                                - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                               - - G GAC CTG CAG CAG CTG GAT GAC ACC ACC CAG - #CTT CCA CTT CTC TCA             46                                                                          Asp Leu Gln Gln Leu Asp Asp Thr Thr G - #ln Leu Pro Leu Leu Ser                 1              - # 5                 - # 10                 - # 15         - - CAC TTT GCC GAA ACC GTA GAA GGA CTC ACC AC - #C ATC CGG GCC TTC AGG           94                                                                       His Phe Ala Glu Thr Val Glu Gly Leu Thr Th - #r Ile Arg Ala Phe Arg                            20 - #                 25 - #                 30              - - TAT GAG GCC CGG TTC CAG CAG AAG CTT CTC GA - #A TAC ACA GAC TCC AAC          142                                                                       Tyr Glu Ala Arg Phe Gln Gln Lys Leu Leu Gl - #u Tyr Thr Asp Ser Asn                        35     - #             40     - #             45                  - - AAC ATT GCT TCC CTC TTC CTC ACA GCT GCC AA - #C AGA TGG CTG GAA GTC          190                                                                       Asn Ile Ala Ser Leu Phe Leu Thr Ala Ala As - #n Arg Trp Leu Glu Val                    50         - #         55         - #         60                      - - CGA ATG GAG TAC ATC GGT GCA TGT GTG GTG CT - #C ATC GCA GCG GTG ACC          238                                                                       Arg Met Glu Tyr Ile Gly Ala Cys Val Val Le - #u Ile Ala Ala Val Thr                65             - #     70             - #     75                          - - TCC ATC TCC AAC TCC CTG CAC AGG GAG CTC TC - #T GCT GGC CTG GTG GGC          286                                                                       Ser Ile Ser Asn Ser Leu His Arg Glu Leu Se - #r Ala Gly Leu Val Gly            80                 - # 85                 - # 90                 - # 95       - - CTG GGC CTT ACC TAC GCC CTA ATG GTC TCC AA - #C TAC CTC AAC TGG ATG          334                                                                       Leu Gly Leu Thr Tyr Ala Leu Met Val Ser As - #n Tyr Leu Asn Trp Met                           100  - #               105  - #               110              - - GTG AGG AAC CTG GCA GAC ATG GAG CTC CAG CT - #G GGG GCT GTG AAG CGC          382                                                                       Val Arg Asn Leu Ala Asp Met Glu Leu Gln Le - #u Gly Ala Val Lys Arg                       115      - #           120      - #           125                  - - ATC CAT GGG CTC CTG AAA ACC GAG GCA GAG AG - #C TAC GAG GGA CTC CTG          430                                                                       Ile His Gly Leu Leu Lys Thr Glu Ala Glu Se - #r Tyr Glu Gly Leu Leu                   130          - #       135          - #       140                      - - GCA CCA TCG CTG ATC CCA AAG AAC TGG CCA GA - #C CAA GGG AAG ATC CAG          478                                                                       Ala Pro Ser Leu Ile Pro Lys Asn Trp Pro As - #p Gln Gly Lys Ile Gln               145              - #   150              - #   155                          - - ATC CAG AAC CTG AGC GTG CGC TAC GAC AGC TC - #C CTG AAG CCG GTG CTG          526                                                                       Ile Gln Asn Leu Ser Val Arg Tyr Asp Ser Se - #r Leu Lys Pro Val Leu           160                 1 - #65                 1 - #70                 1 -      #75                                                                              - - AAG CAC GTC AAT GCC CTC ATC TCC CCT GGA CA - #G AAG ATC GGG ATC        TGC      574                                                                    Lys His Val Asn Ala Leu Ile Ser Pro Gly Gl - #n Lys Ile Gly Ile Cys                          180  - #               185  - #               190              - - GGC CGC ACC GGC AGT GGG AAG TCC TCC TTC TC - #T CTT GCC TTC TTC CGC          622                                                                       Gly Arg Thr Gly Ser Gly Lys Ser Ser Phe Se - #r Leu Ala Phe Phe Arg                       195      - #           200      - #           205                  - - ATG GTG GAC ACG TTC GAA GGG CAC ATC ATC AT - #T GAT GGC ATT GAC ATC          670                                                                       Met Val Asp Thr Phe Glu Gly His Ile Ile Il - #e Asp Gly Ile Asp Ile                   210          - #       215          - #       220                      - - GCC AAA CTG CCG CTG CAC ACC CTG CGC TCA CG - #C CTC TCC ATC ATC CTG          718                                                                       Ala Lys Leu Pro Leu His Thr Leu Arg Ser Ar - #g Leu Ser Ile Ile Leu               225              - #   230              - #   235                          - - CAG GAC CCC GTC CTC TTC AGC GGC ACC ATC CG - #A TTT AAC CTG GAC CCT          766                                                                       Gln Asp Pro Val Leu Phe Ser Gly Thr Ile Ar - #g Phe Asn Leu Asp Pro           240                 2 - #45                 2 - #50                 2 -      #55                                                                              - - GAG AGG AAG TGC TCA GAT AGC ACA CTG TGG GA - #G GCC CTG GAA ATC        GCC      814                                                                    Glu Arg Lys Cys Ser Asp Ser Thr Leu Trp Gl - #u Ala Leu Glu Ile Ala                          260  - #               265  - #               270              - - CAG CTG AAG CTG GTG GTG AAG GCA CTG CCA GG - #A GGC CTC GAT GCC ATC          862                                                                       Gln Leu Lys Leu Val Val Lys Ala Leu Pro Gl - #y Gly Leu Asp Ala Ile                       275      - #           280      - #           285                  - - ATC ACA GAA GGC GGG GAG AAT TTC AGC CAG GG - #A CAG AGG CAG CTG TTC          910                                                                       Ile Thr Glu Gly Gly Glu Asn Phe Ser Gln Gl - #y Gln Arg Gln Leu Phe                   290          - #       295          - #       300                      - - TGC CTG GCC CGG GCC TTC GTG AGG AAG ACC AG - #C ATC TTC ATC ATG GAC          958                                                                       Cys Leu Ala Arg Ala Phe Val Arg Lys Thr Se - #r Ile Phe Ile Met Asp               305              - #   310              - #   315                          - - GAG GCC ACG GCT TCC ATT GAC ATG GCC ACG GA - #A AAC ATC CTC CAA AAG         1006                                                                       Glu Ala Thr Ala Ser Ile Asp Met Ala Thr Gl - #u Asn Ile Leu Gln Lys           320                 3 - #25                 3 - #30                 3 -      #35                                                                              - - GTG GTG ATG ACA GCC TTC GCA GAC CGC ACT GT - #G GTC ACC ATC GCG        CAT     1054                                                                    Val Val Met Thr Ala Phe Ala Asp Arg Thr Va - #l Val Thr Ile Ala His                          340  - #               345  - #               350              - - CGA GTG CAC ACC ATC CTG AGT GCA GAC CTG GT - #G ATC GTC CTG AAG CGG         1102                                                                       Arg Val His Thr Ile Leu Ser Ala Asp Leu Va - #l Ile Val Leu Lys Arg                       355      - #           360      - #           365                  - - GGT GCC ATC CTT GAG TTC GAT AAG CCA GAG AA - #G CTG CTC AGC CGG AAG         1150                                                                       Gly Ala Ile Leu Glu Phe Asp Lys Pro Glu Ly - #s Leu Leu Ser Arg Lys                   370          - #       375          - #       380                      - - GAC AGC GTC TTC GCC TCC TTC GTC CGT GCA GA - #C AAG TGACCTGCCA              1196                                                                       Asp Ser Val Phe Ala Ser Phe Val Arg Ala As - #p Lys                               385              - #   390              - #   395                          - - GAGCCCAAGT GCCATCCCAC ATTCGGACCC TGCCCATACC CCTGCCTGGG TT -             #TTCTAACT   1256                                                                 - - GTAAATCACT TGTAAATAAA TAGATTTGAT TATTTCCTAA AAAAAAAAAA AA - #               1308                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:3:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 395 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                               - - Asp Leu Gln Gln Leu Asp Asp Thr Thr Gln Le - #u Pro Leu Leu Ser His        1               5 - #                 10 - #                 15              - - Phe Ala Glu Thr Val Glu Gly Leu Thr Thr Il - #e Arg Ala Phe Arg Tyr                   20     - #             25     - #             30                  - - Glu Ala Arg Phe Gln Gln Lys Leu Leu Glu Ty - #r Thr Asp Ser Asn Asn               35         - #         40         - #         45                      - - Ile Ala Ser Leu Phe Leu Thr Ala Ala Asn Ar - #g Trp Leu Glu Val Arg           50             - #     55             - #     60                          - - Met Glu Tyr Ile Gly Ala Cys Val Val Leu Il - #e Ala Ala Val Thr Ser       65                 - # 70                 - # 75                 - # 80       - - Ile Ser Asn Ser Leu His Arg Glu Leu Ser Al - #a Gly Leu Val Gly Leu                       85 - #                 90 - #                 95              - - Gly Leu Thr Tyr Ala Leu Met Val Ser Asn Ty - #r Leu Asn Trp Met Val                  100      - #           105      - #           110                  - - Arg Asn Leu Ala Asp Met Glu Leu Gln Leu Gl - #y Ala Val Lys Arg Ile              115          - #       120          - #       125                      - - His Gly Leu Leu Lys Thr Glu Ala Glu Ser Ty - #r Glu Gly Leu Leu Ala          130              - #   135              - #   140                          - - Pro Ser Leu Ile Pro Lys Asn Trp Pro Asp Gl - #n Gly Lys Ile Gln Ile      145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - Gln Asn Leu Ser Val Arg Tyr Asp Ser Ser Le - #u Lys Pro Val Leu        Lys                                                                                             165  - #               170  - #               175             - - His Val Asn Ala Leu Ile Ser Pro Gly Gln Ly - #s Ile Gly Ile Cys Gly                  180      - #           185      - #           190                  - - Arg Thr Gly Ser Gly Lys Ser Ser Phe Ser Le - #u Ala Phe Phe Arg Met              195          - #       200          - #       205                      - - Val Asp Thr Phe Glu Gly His Ile Ile Ile As - #p Gly Ile Asp Ile Ala          210              - #   215              - #   220                          - - Lys Leu Pro Leu His Thr Leu Arg Ser Arg Le - #u Ser Ile Ile Leu Gln      225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - Asp Pro Val Leu Phe Ser Gly Thr Ile Arg Ph - #e Asn Leu Asp Pro        Glu                                                                                             245  - #               250  - #               255             - - Arg Lys Cys Ser Asp Ser Thr Leu Trp Glu Al - #a Leu Glu Ile Ala Gln                  260      - #           265      - #           270                  - - Leu Lys Leu Val Val Lys Ala Leu Pro Gly Gl - #y Leu Asp Ala Ile Ile              275          - #       280          - #       285                      - - Thr Glu Gly Gly Glu Asn Phe Ser Gln Gly Gl - #n Arg Gln Leu Phe Cys          290              - #   295              - #   300                          - - Leu Ala Arg Ala Phe Val Arg Lys Thr Ser Il - #e Phe Ile Met Asp Glu      305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - Ala Thr Ala Ser Ile Asp Met Ala Thr Glu As - #n Ile Leu Gln Lys        Val                                                                                             325  - #               330  - #               335             - - Val Met Thr Ala Phe Ala Asp Arg Thr Val Va - #l Thr Ile Ala His Arg                  340      - #           345      - #           350                  - - Val His Thr Ile Leu Ser Ala Asp Leu Val Il - #e Val Leu Lys Arg Gly              355          - #       360          - #       365                      - - Ala Ile Leu Glu Phe Asp Lys Pro Glu Lys Le - #u Leu Ser Arg Lys Asp          370              - #   375              - #   380                          - - Ser Val Phe Ala Ser Phe Val Arg Ala Asp Ly - #s                          385                 3 - #90                 3 - #95                            - -  - - (2) INFORMATION FOR SEQ ID NO:4:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5110 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                               - - CCCTTGTGAC AGGTCAGTCT TACGAGAATA TGGTAACTGA GATCATGTCA AT -             #GGGCTATG     60                                                                 - - AACGAGAACA AGTAATTGCA GCCCTGAGAG CCAGCTTCAA CAACCCTGAT AG -            #AGCTGTGG    120                                                                 - - AATATCTTCT AATGGGAATC CCTGGAGACT GAGGAGTTCC AGTACTCACA GC -            #CTGTGGAG    180                                                                 - - GAGGATCAAC CACGGCCTGA CTTTCGCGGC CGCCGCGGGA GGCGCGCGGA GC -            #CGGAGCCG    240                                                                 - - AGCCCGTGCG CGCGCCACCA TGCCTTTGGC CTTCTGCGGC ACCGAGAACC AC -            #TCGGCCGC    300                                                                 - - CTACCGGGTG GACCAAGGCG TCCTCAACAA CGGCTGCTTC GTGGACGCGC TC -            #AATGTGGT    360                                                                 - - GCCACATGTC TTTCTGCTCT TCATCACCTT CCCCATCCTC TTCATCGGAT GG -            #GGCAGCCA    420                                                                 - - GAGCTCCAAG GTGCACATTC ACCACAGCAC CTGGCTCCAT TTCCCGGGGC AC -            #AACCTGCG    480                                                                 - - CTGGATCCTG ACCTTCATAC TGCTCTTCGT CCTCGTGTGT GAGATCGCTG AG -            #GGTATCCT    540                                                                 - - GTCTGACGGG GTGACAGAAT CCCGCCACCT CCACTTATAC ATGCCAGCTG GG -            #ATGGCATT    600                                                                 - - CATGGCTGCC ATCACCTCTG TGGTCTACTA CCATAACATT GAGACCTCTA AC -            #TTTCCCAA    660                                                                 - - GCTGCTGATT GCTCTGCTCA TCTACTGGAC CCTGGCCTTC ATCACGAAGA CC -            #ATCAAGTT    720                                                                 - - CGTCAAGTTC TACGACCACG CCATTGGCTT CTCTCAGCTG CGCTTCTGCC TC -            #ACGGGGCT    780                                                                 - - TCTGGTGATC CTCTACGGGA TGCTGCTGCT TGTGGAGGTC AATGTCATCC GG -            #GTGAGGAG    840                                                                 - - ATACGTCTTC TTCAAGACAC CAAGGGAAGT AAAGCCCCCC GAGGACCTAC AG -            #GACCTGGG    900                                                                 - - TGTGCGCTTT CTGCAGCCCT TCGTTAACCT GCTATCAAAG GGGACCTACT GG -            #TGGATGAA    960                                                                 - - TGCCTTCATC AAGACTGCTC ACAAGAAGCC CATCGACCTG CGGGCCATCG GG -            #AAGCTGCC   1020                                                                 - - CATTGCCATG AGAGCCCTCA CCAACTACCA GCGACTCTGC TTGGCCTTCG AT -            #GCCCAGGC   1080                                                                 - - GCGGAAGGAC ACACAGAGCC AGCAGGGTGC CCGGGCCATC TGGAGGGCTC TC -            #TGTCATGC   1140                                                                 - - CTTTGGGAGA CGGCTGGTCC TCAGCAGCAC ATTCCGTATC CTGGCCGACC TC -            #CTGGGCTT   1200                                                                 - - TGCTGGGCCA CTCTGCATCT TCGGGATCGT GGACCACCTC GGGAAGGAGA AC -            #CACGTCTT   1260                                                                 - - CCAGCCCAAG ACACAGTTTC TTGGAGTTTA CTTTGTCTCA TCCCAAGAGT TC -            #CTCGGCAA   1320                                                                 - - TGCCTATGTC TTGGCTGTTC TTCTGTTCCT TGCCCTCCTG CTGCAAAGGA CC -            #TTTCTACA   1380                                                                 - - AGCCTCGTAC TACGTTGCCA TTGAAACTGG GATCAACCTG AGAGGAGCAA TC -            #CAGACCAA   1440                                                                 - - GATTTACAAT AAGATCATGC ACTTGTCTAC TTCCAACCTG TCCATGGGGG AA -            #ATGACTGC   1500                                                                 - - TGGGCAGATC TGCAACCTGG TGGCCATCGA CACCAACCAG CTCATGTGGT TT -            #TTCTTCTT   1560                                                                 - - ATGCCCAAAC CTCTGGGCTA TGCCGGTACA GATCATTGTG GGCGTGATCC TC -            #CTCTACTA   1620                                                                 - - CATCCTTGGG GTCAGCGCCT TGATTGGAGC GGCTGTCATC ATTCTGCTGG CT -            #CCTGTACA   1680                                                                 - - GTACTTTGTG GCCACCAAGC TGTCCCAGGC ACAGCGGACG ACCCTGGAAT AT -            #TCCAATGA   1740                                                                 - - GAGGCTGAAG CAGACCAATG AGATGCTCCG GGGCATCAAG TTGCTCAAGC TC -            #TATGCGTG   1800                                                                 - - GGAGAACATC TTCTGCTCCA GGGTGGAGAA GACACGCAGG AAGGAAATGA CC -            #AGCCTCAG   1860                                                                 - - GGCCTTCGCT GTCTACACCT CCATCTCCAT CTTCATGAAC ACAGCTATCC CC -            #ATCGCTGC   1920                                                                 - - TGTCCTCATC ACCTTCGTGG GCCACGTCAG CTTCTTCAAA GAGTCGGACT TC -            #TCGCCCTC   1980                                                                 - - GGTGGCCTTT GCCTCTCTCT CTCTCTTCCA CATCCTGGTC ACACCGCTGT TC -            #CTGCTGTC   2040                                                                 - - TAGTGTGGTT CGGTCCACTG TCAAGGCCCT GGTGAGCGTG CAAAAGCTGA GT -            #GAGTTCCT   2100                                                                 - - GTCCAGTGCA GAGATCCGTG AGGAACAGTG TGCCCCCCGA GAGCCCGCAC CC -            #CAAGGCCA   2160                                                                 - - AGCGGGCAAG TACCAGGCGG TGCCCCTCAA GGTCGTAAAC CGCAAGCGCC CA -            #GCCCGAGA   2220                                                                 - - AGAAGTCCGG GACCTCTTGG GCCCACTGCA GAGGCTGACT CCCAGCACGG AT -            #GGAGACGC   2280                                                                 - - TGACAACTTC TGTGTCCAGA TCATCGGAGG CTTCTTCACC TGGACCCCTG AT -            #GGAATCCC   2340                                                                 - - CACCCTGTCC AACATCACCA TCCGTATCCC CCGAGGTCAG CTGACCATGA TC -            #GTGGGGCA   2400                                                                 - - GGTGGGCTGT GGCAAGTCCT CGCTCCTTCT GGCCACCCTG GGGGAGATGC AG -            #AAGGTCTC   2460                                                                 - - TGGAGCTGTC TTCTGGAACA GCCTTCCAGA CAGCGAGGGG AGAAGACCCC AG -            #CAACCCAG   2520                                                                 - - AGCGGGAGAC AGCGGCCGAT TCGGATGCCA GGAGCAGAGG CCCTGTGGCT AC -            #GCATCTCA   2580                                                                 - - GAAACCATGG CTGCTAAATG CCACTGTGGA GGAGAACATC ACCTTCGAGA GT -            #CCCTTCAA   2640                                                                 - - TAAGCAACGG TACAAGATGG TCATCGAAGC CTGCTCCCTG CAGCCAGACA TA -            #GACATCCT   2700                                                                 - - GCCCCATGGA GACCAGACTC AGATTGGGGA ACGAGGCATC AACTTGAGTA CT -            #GGTGGTCA   2760                                                                 - - GCGTCCAGAT CAGTGTAGAC CCGAGCCCTC TACCAGCACA CCAATGATTG TC -            #TTTTTGGA   2820                                                                 - - TGACCCTTTC TCGGCTCTGG ATGTCCATCT GAGTGACCAC CTAATGCAGG CT -            #GGCATCCT   2880                                                                 - - CGAGCTGCTC CGGGATGACA AGAGGACAGT GGTCTTGGTG ACCCACAAGC TA -            #CAGTACCT   2940                                                                 - - GCCTCATGCT GACTGGATCA TTGCTATGAA GGATGGCACC ATTCAGAGGG AG -            #GGGACACT   3000                                                                 - - CAAGGACTTC CAGAGGTCTG AGTGCCAGCT CTTTGAGCAT TGGAAGACCC TC -            #ATGAACCG   3060                                                                 - - GCAGGACCAA GAGCTGGAGA AGGAGACAGT CATGGAGAGA AAAGCCCCAG AG -            #CCATCTCA   3120                                                                 - - GGGCCTGCCC CGTGCCATGT CCTCAAGAGA TGGCCTTCTG CTGGATGAGG AT -            #GAGGAGGA   3180                                                                 - - AGAGGAGGCA GCCGAGAGCG AGGAAGATGA CAACTTATCC TCTGTGCTGC AT -            #CAGCGAGC   3240                                                                 - - CAAGATCCCA TGGCGAGCCT GCACCAAGTA TTTGTCCTCT GCTGGCATCC TG -            #CTCCTGTC   3300                                                                 - - CCTGCTTGTC TTCTCCCAGC TGCTCAAGCA CATGGTCTTG GTGGCCATTG AC -            #TACTGGCT   3360                                                                 - - GGCCAAGTGG ACGGACAGTG CCCTGGTCCT GAGCCCCGCC GCCAGGAACT GC -            #TCCCTCAG   3420                                                                 - - CCAGGAATGT GCCCTGGACC AATCTGTCTA TGCCATGGTA TTCACCGTGC TC -            #TGCAGCCT   3480                                                                 - - GGGTATCGCG CTGTGCCTTG TCACCTCTGT CACTGTGGAG TGGACGGGAC TG -            #AAGGTGGC   3540                                                                 - - CAAGAGGCTG CATCGCAGCC TGCTCAACCG TATCATCCTG GCTCCCATGA GG -            #TTCTTTGA   3600                                                                 - - GACCACGCCC CTGGGGAGTA TCCTGAACAG ATTTTCATCT GACTGTAACA CC -            #ATTGACCA   3660                                                                 - - GCATATCCCG TCCACGCTGG AGTGCCTGAG CAGATCCACC TTACTCTGTG TC -            #TCCGCCCT   3720                                                                 - - GGCTGTCATC TCCTACGTCA CGCCTGTGTT CCTAGTGGCC CTCTTACCCC TC -            #GCCGTCGT   3780                                                                 - - GTGCTACTTC ATCCAGAAGT ACTTCCGAGT GGCGTCCAGG GACCTGCAGC AG -            #CTGGACGA   3840                                                                 - - CACAACACAG CTCCCTCTGC TCTCACACTT TGCTGAAACT GTGGAAGGAC TC -            #ACCACCAT   3900                                                                 - - CCGTGCCTTC AGGTACGAGG CCCGGTTCCA GCAGAAGCTC CTAGAGTACA CC -            #GACTCCAA   3960                                                                 - - CAACATTGCC TCTCTCTTCC TCACAGCAGC CAACAGGTGG CTGGAAGTCC GC -            #ATGGAGTA   4020                                                                 - - CATCGGAGCA TGCGTGGTAC TCATCGCCGC TGCCACCTCC ATCTCCAACT CC -            #CTACACAG   4080                                                                 - - GGAGCTCTCA GCCGGCCTAG TAGGCCTGGG CCTCACCTAT GCCTTGATGG TC -            #TCCAACTA   4140                                                                 - - CCTCAACTGG ATGGTGAGGA ACCTGGCAGA CATGGAGATC CAACTGGGAG CT -            #GTGAAGGG   4200                                                                 - - TATCCACACA CTCCTGAAAA CTGAGGCAGA GAGCTATGAG GGGCTCCTGG CA -            #CCATCGCT   4260                                                                 - - GATCCCCAAG AACTGGCCAG ACCAAGGGAA GATCCAAATT CAAAACCTGA GT -            #GTACGCTA   4320                                                                 - - TGACAGCTCC CTGAAGCCCG TGCTGAAGCA CGTCAACGCC CTCATCTCCC CA -            #GGACAGAA   4380                                                                 - - GATTGGGATC TGCGGCCGCA CAGGCAGTGG AAAATCCTCC TTCTCTCTCG CC -            #TTTTTCCG   4440                                                                 - - AATGGTGGAT ATGTTTGAAG GGCGTATCAT CATCGATGGC ATTGACATCG CC -            #AAGCTGCC   4500                                                                 - - GCTGCACACG CTCGGCTCAC GCCTGTCTAT CATCCTACAG GACCCTGTTC TC -            #TTCAGTGG   4560                                                                 - - TACCATCAGA TTCAACCTGG ACCCAGAGAA GAAATGCTCA GACAGCACGC TG -            #TGGGAGGC   4620                                                                 - - TCTGGAGATC GCTCAGCTGA AGCTGGTGGT GAAGGCCCTG CCAGGAGGCC TG -            #GATGCCAT   4680                                                                 - - CATCACGGAA GGAGGGGAGA ATTTTAGCCA GGGCCAGAGG CAGCTGTTCT GC -            #CTGGCCCG   4740                                                                 - - GGCCTTTGTG AGGAAGACCA GCATCTTCAT CATGGATGAA GCAACTGCCT CC -            #ATCGACAT   4800                                                                 - - GGCTACGGAA AATATCCTCC AGAAGGTGGT GATGACAGCC TTCGCAGACC GC -            #ACCGTGGT   4860                                                                 - - CACCATCGCG CACCGCGTGC ACACCATCCT GAGTGCAGAC CTAGTGATGG TC -            #CTGAAGAG   4920                                                                 - - GGGCGCGATC CTGGAGTTCG ACAAGCCGGA AAAGCTTCTC AGCCAGAAGG AC -            #AGCGTCTT   4980                                                                 - - TGCCTCCTTT GTCCGCGCGG ACAAATGACC AGCCAGCGCC AAAGTGCCAC CC -            #CACACCTC   5040                                                                 - - ACCTGCTTGC CATGGATTTC TTACTGTAAA TCACTTGTAA ATAAAGAAAC TA -            #ATTCTTTG   5100                                                                 - - CTAAAAAAAA                - #                  - #                      - #      5110                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:5:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5110 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 260..5004                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                               - - CCCTTGTGAC AGGTCAGTCT TACGAGAATA TGGTAACTGA GATCATGTCA AT -             #GGGCTATG     60                                                                 - - AACGAGAACA AGTAATTGCA GCCCTGAGAG CCAGCTTCAA CAACCCTGAT AG -            #AGCTGTGG    120                                                                 - - AATATCTTCT AATGGGAATC CCTGGAGACT GAGGAGTTCC AGTACTCACA GC -            #CTGTGGAG    180                                                                 - - GAGGATCAAC CACGGCCTGA CTTTCGCGGC CGCCGCGGGA GGCGCGCGGA GC -            #CGGAGCCG    240                                                                 - - AGCCCGTGCG CGCGCCACC ATG CCT TTG GCC TTC TGC GGC - # ACC GAG AAC       CAC     292                                                                                       - #  Met Pro Leu Ala Phe Cys Gly Thr Glu - #Asn His                          - #    1              - # 5                 - # 10           - - TCG GCC GCC TAC CGG GTG GAC CAA GGC GTC CT - #C AAC AAC GGC TGC TTC          340                                                                       Ser Ala Ala Tyr Arg Val Asp Gln Gly Val Le - #u Asn Asn Gly Cys Phe                        15     - #             20     - #             25                  - - GTG GAC GCG CTC AAT GTG GTG CCA CAT GTC TT - #T CTG CTC TTC ATC ACC          388                                                                       Val Asp Ala Leu Asn Val Val Pro His Val Ph - #e Leu Leu Phe Ile Thr                    30         - #         35         - #         40                      - - TTC CCC ATC CTC TTC ATC GGA TGG GGC AGC CA - #G AGC TCC AAG GTG CAC          436                                                                       Phe Pro Ile Leu Phe Ile Gly Trp Gly Ser Gl - #n Ser Ser Lys Val His                45             - #     50             - #     55                          - - ATT CAC CAC AGC ACC TGG CTC CAT TTC CCG GG - #G CAC AAC CTG CGC TGG          484                                                                       Ile His His Ser Thr Trp Leu His Phe Pro Gl - #y His Asn Leu Arg Trp            60                 - # 65                 - # 70                 - # 75       - - ATC CTG ACC TTC ATA CTG CTC TTC GTC CTC GT - #G TGT GAG ATC GCT GAG          532                                                                       Ile Leu Thr Phe Ile Leu Leu Phe Val Leu Va - #l Cys Glu Ile Ala Glu                            80 - #                 85 - #                 90              - - GGT ATC CTG TCT GAC GGG GTG ACA GAA TCC CG - #C CAC CTC CAC TTA TAC          580                                                                       Gly Ile Leu Ser Asp Gly Val Thr Glu Ser Ar - #g His Leu His Leu Tyr                        95     - #            100     - #            105                  - - ATG CCA GCT GGG ATG GCA TTC ATG GCT GCC AT - #C ACC TCT GTG GTC TAC          628                                                                       Met Pro Ala Gly Met Ala Phe Met Ala Ala Il - #e Thr Ser Val Val Tyr                   110          - #       115          - #       120                      - - TAC CAT AAC ATT GAG ACC TCT AAC TTT CCC AA - #G CTG CTG ATT GCT CTG          676                                                                       Tyr His Asn Ile Glu Thr Ser Asn Phe Pro Ly - #s Leu Leu Ile Ala Leu               125              - #   130              - #   135                          - - CTC ATC TAC TGG ACC CTG GCC TTC ATC ACG AA - #G ACC ATC AAG TTC GTC          724                                                                       Leu Ile Tyr Trp Thr Leu Ala Phe Ile Thr Ly - #s Thr Ile Lys Phe Val           140                 1 - #45                 1 - #50                 1 -      #55                                                                              - - AAG TTC TAC GAC CAC GCC ATT GGC TTC TCT CA - #G CTG CGC TTC TGC        CTC      772                                                                    Lys Phe Tyr Asp His Ala Ile Gly Phe Ser Gl - #n Leu Arg Phe Cys Leu                          160  - #               165  - #               170              - - ACG GGG CTT CTG GTG ATC CTC TAC GGG ATG CT - #G CTG CTT GTG GAG GTC          820                                                                       Thr Gly Leu Leu Val Ile Leu Tyr Gly Met Le - #u Leu Leu Val Glu Val                       175      - #           180      - #           185                  - - AAT GTC ATC CGG GTG AGG AGA TAC GTC TTC TT - #C AAG ACA CCA AGG GAA          868                                                                       Asn Val Ile Arg Val Arg Arg Tyr Val Phe Ph - #e Lys Thr Pro Arg Glu                   190          - #       195          - #       200                      - - GTA AAG CCC CCC GAG GAC CTA CAG GAC CTG GG - #T GTG CGC TTT CTG CAG          916                                                                       Val Lys Pro Pro Glu Asp Leu Gln Asp Leu Gl - #y Val Arg Phe Leu Gln               205              - #   210              - #   215                          - - CCC TTC GTT AAC CTG CTA TCA AAG GGG ACC TA - #C TGG TGG ATG AAT GCC          964                                                                       Pro Phe Val Asn Leu Leu Ser Lys Gly Thr Ty - #r Trp Trp Met Asn Ala           220                 2 - #25                 2 - #30                 2 -      #35                                                                              - - TTC ATC AAG ACT GCT CAC AAG AAG CCC ATC GA - #C CTG CGG GCC ATC        GGG     1012                                                                    Phe Ile Lys Thr Ala His Lys Lys Pro Ile As - #p Leu Arg Ala Ile Gly                          240  - #               245  - #               250              - - AAG CTG CCC ATT GCC ATG AGA GCC CTC ACC AA - #C TAC CAG CGA CTC TGC         1060                                                                       Lys Leu Pro Ile Ala Met Arg Ala Leu Thr As - #n Tyr Gln Arg Leu Cys                       255      - #           260      - #           265                  - - TTG GCC TTC GAT GCC CAG GCG CGG AAG GAC AC - #A CAG AGC CAG CAG GGT         1108                                                                       Leu Ala Phe Asp Ala Gln Ala Arg Lys Asp Th - #r Gln Ser Gln Gln Gly                   270          - #       275          - #       280                      - - GCC CGG GCC ATC TGG AGG GCT CTC TGT CAT GC - #C TTT GGG AGA CGG CTG         1156                                                                       Ala Arg Ala Ile Trp Arg Ala Leu Cys His Al - #a Phe Gly Arg Arg Leu               285              - #   290              - #   295                          - - GTC CTC AGC AGC ACA TTC CGT ATC CTG GCC GA - #C CTC CTG GGC TTT GCT         1204                                                                       Val Leu Ser Ser Thr Phe Arg Ile Leu Ala As - #p Leu Leu Gly Phe Ala           300                 3 - #05                 3 - #10                 3 -      #15                                                                              - - GGG CCA CTC TGC ATC TTC GGG ATC GTG GAC CA - #C CTC GGG AAG GAG        AAC     1252                                                                    Gly Pro Leu Cys Ile Phe Gly Ile Val Asp Hi - #s Leu Gly Lys Glu Asn                          320  - #               325  - #               330              - - CAC GTC TTC CAG CCC AAG ACA CAG TTT CTT GG - #A GTT TAC TTT GTC TCA         1300                                                                       His Val Phe Gln Pro Lys Thr Gln Phe Leu Gl - #y Val Tyr Phe Val Ser                       335      - #           340      - #           345                  - - TCC CAA GAG TTC CTC GGC AAT GCC TAT GTC TT - #G GCT GTT CTT CTG TTC         1348                                                                       Ser Gln Glu Phe Leu Gly Asn Ala Tyr Val Le - #u Ala Val Leu Leu Phe                   350          - #       355          - #       360                      - - CTT GCC CTC CTG CTG CAA AGG ACC TTT CTA CA - #A GCC TCG TAC TAC GTT         1396                                                                       Leu Ala Leu Leu Leu Gln Arg Thr Phe Leu Gl - #n Ala Ser Tyr Tyr Val               365              - #   370              - #   375                          - - GCC ATT GAA ACT GGG ATC AAC CTG AGA GGA GC - #A ATC CAG ACC AAG ATT         1444                                                                       Ala Ile Glu Thr Gly Ile Asn Leu Arg Gly Al - #a Ile Gln Thr Lys Ile           380                 3 - #85                 3 - #90                 3 -      #95                                                                              - - TAC AAT AAG ATC ATG CAC TTG TCT ACT TCC AA - #C CTG TCC ATG GGG        GAA     1492                                                                    Tyr Asn Lys Ile Met His Leu Ser Thr Ser As - #n Leu Ser Met Gly Glu                          400  - #               405  - #               410              - - ATG ACT GCT GGG CAG ATC TGC AAC CTG GTG GC - #C ATC GAC ACC AAC CAG         1540                                                                       Met Thr Ala Gly Gln Ile Cys Asn Leu Val Al - #a Ile Asp Thr Asn Gln                       415      - #           420      - #           425                  - - CTC ATG TGG TTT TTC TTC TTA TGC CCA AAC CT - #C TGG GCT ATG CCG GTA         1588                                                                       Leu Met Trp Phe Phe Phe Leu Cys Pro Asn Le - #u Trp Ala Met Pro Val                   430          - #       435          - #       440                      - - CAG ATC ATT GTG GGC GTG ATC CTC CTC TAC TA - #C ATC CTT GGG GTC AGC         1636                                                                       Gln Ile Ile Val Gly Val Ile Leu Leu Tyr Ty - #r Ile Leu Gly Val Ser               445              - #   450              - #   455                          - - GCC TTG ATT GGA GCG GCT GTC ATC ATT CTG CT - #G GCT CCT GTA CAG TAC         1684                                                                       Ala Leu Ile Gly Ala Ala Val Ile Ile Leu Le - #u Ala Pro Val Gln Tyr           460                 4 - #65                 4 - #70                 4 -      #75                                                                              - - TTT GTG GCC ACC AAG CTG TCC CAG GCA CAG CG - #G ACG ACC CTG GAA        TAT     1732                                                                    Phe Val Ala Thr Lys Leu Ser Gln Ala Gln Ar - #g Thr Thr Leu Glu Tyr                          480  - #               485  - #               490              - - TCC AAT GAG AGG CTG AAG CAG ACC AAT GAG AT - #G CTC CGG GGC ATC AAG         1780                                                                       Ser Asn Glu Arg Leu Lys Gln Thr Asn Glu Me - #t Leu Arg Gly Ile Lys                       495      - #           500      - #           505                  - - TTG CTC AAG CTC TAT GCG TGG GAG AAC ATC TT - #C TGC TCC AGG GTG GAG         1828                                                                       Leu Leu Lys Leu Tyr Ala Trp Glu Asn Ile Ph - #e Cys Ser Arg Val Glu                   510          - #       515          - #       520                      - - AAG ACA CGC AGG AAG GAA ATG ACC AGC CTC AG - #G GCC TTC GCT GTC TAC         1876                                                                       Lys Thr Arg Arg Lys Glu Met Thr Ser Leu Ar - #g Ala Phe Ala Val Tyr               525              - #   530              - #   535                          - - ACC TCC ATC TCC ATC TTC ATG AAC ACA GCT AT - #C CCC ATC GCT GCT GTC         1924                                                                       Thr Ser Ile Ser Ile Phe Met Asn Thr Ala Il - #e Pro Ile Ala Ala Val           540                 5 - #45                 5 - #50                 5 -      #55                                                                              - - CTC ATC ACC TTC GTG GGC CAC GTC AGC TTC TT - #C AAA GAG TCG GAC        TTC     1972                                                                    Leu Ile Thr Phe Val Gly His Val Ser Phe Ph - #e Lys Glu Ser Asp Phe                          560  - #               565  - #               570              - - TCG CCC TCG GTG GCC TTT GCC TCT CTC TCT CT - #C TTC CAC ATC CTG GTC         2020                                                                       Ser Pro Ser Val Ala Phe Ala Ser Leu Ser Le - #u Phe His Ile Leu Val                       575      - #           580      - #           585                  - - ACA CCG CTG TTC CTG CTG TCT AGT GTG GTT CG - #G TCC ACT GTC AAG GCC         2068                                                                       Thr Pro Leu Phe Leu Leu Ser Ser Val Val Ar - #g Ser Thr Val Lys Ala                   590          - #       595          - #       600                      - - CTG GTG AGC GTG CAA AAG CTG AGT GAG TTC CT - #G TCC AGT GCA GAG ATC         2116                                                                       Leu Val Ser Val Gln Lys Leu Ser Glu Phe Le - #u Ser Ser Ala Glu Ile               605              - #   610              - #   615                          - - CGT GAG GAA CAG TGT GCC CCC CGA GAG CCC GC - #A CCC CAA GGC CAA GCG         2164                                                                       Arg Glu Glu Gln Cys Ala Pro Arg Glu Pro Al - #a Pro Gln Gly Gln Ala           620                 6 - #25                 6 - #30                 6 -      #35                                                                              - - GGC AAG TAC CAG GCG GTG CCC CTC AAG GTC GT - #A AAC CGC AAG CGC        CCA     2212                                                                    Gly Lys Tyr Gln Ala Val Pro Leu Lys Val Va - #l Asn Arg Lys Arg Pro                          640  - #               645  - #               650              - - GCC CGA GAA GAA GTC CGG GAC CTC TTG GGC CC - #A CTG CAG AGG CTG ACT         2260                                                                       Ala Arg Glu Glu Val Arg Asp Leu Leu Gly Pr - #o Leu Gln Arg Leu Thr                       655      - #           660      - #           665                  - - CCC AGC ACG GAT GGA GAC GCT GAC AAC TTC TG - #T GTC CAG ATC ATC GGA         2308                                                                       Pro Ser Thr Asp Gly Asp Ala Asp Asn Phe Cy - #s Val Gln Ile Ile Gly                   670          - #       675          - #       680                      - - GGC TTC TTC ACC TGG ACC CCT GAT GGA ATC CC - #C ACC CTG TCC AAC ATC         2356                                                                       Gly Phe Phe Thr Trp Thr Pro Asp Gly Ile Pr - #o Thr Leu Ser Asn Ile               685              - #   690              - #   695                          - - ACC ATC CGT ATC CCC CGA GGT CAG CTG ACC AT - #G ATC GTG GGG CAG GTG         2404                                                                       Thr Ile Arg Ile Pro Arg Gly Gln Leu Thr Me - #t Ile Val Gly Gln Val           700                 7 - #05                 7 - #10                 7 -      #15                                                                              - - GGC TGT GGC AAG TCC TCG CTC CTT CTG GCC AC - #C CTG GGG GAG ATG        CAG     2452                                                                    Gly Cys Gly Lys Ser Ser Leu Leu Leu Ala Th - #r Leu Gly Glu Met Gln                          720  - #               725  - #               730              - - AAG GTC TCT GGA GCT GTC TTC TGG AAC AGC CT - #T CCA GAC AGC GAG GGG         2500                                                                       Lys Val Ser Gly Ala Val Phe Trp Asn Ser Le - #u Pro Asp Ser Glu Gly                       735      - #           740      - #           745                  - - AGA AGA CCC CAG CAA CCC AGA GCG GGA GAC AG - #C GGC CGA TTC GGA TGC         2548                                                                       Arg Arg Pro Gln Gln Pro Arg Ala Gly Asp Se - #r Gly Arg Phe Gly Cys                   750          - #       755          - #       760                      - - CAG GAG CAG AGG CCC TGT GGC TAC GCA TCT CA - #G AAA CCA TGG CTG CTA         2596                                                                       Gln Glu Gln Arg Pro Cys Gly Tyr Ala Ser Gl - #n Lys Pro Trp Leu Leu               765              - #   770              - #   775                          - - AAT GCC ACT GTG GAG GAG AAC ATC ACC TTC GA - #G AGT CCC TTC AAT AAG         2644                                                                       Asn Ala Thr Val Glu Glu Asn Ile Thr Phe Gl - #u Ser Pro Phe Asn Lys           780                 7 - #85                 7 - #90                 7 -      #95                                                                              - - CAA CGG TAC AAG ATG GTC ATC GAA GCC TGC TC - #C CTG CAG CCA GAC        ATA     2692                                                                    Gln Arg Tyr Lys Met Val Ile Glu Ala Cys Se - #r Leu Gln Pro Asp Ile                          800  - #               805  - #               810              - - GAC ATC CTG CCC CAT GGA GAC CAG ACT CAG AT - #T GGG GAA CGA GGC ATC         2740                                                                       Asp Ile Leu Pro His Gly Asp Gln Thr Gln Il - #e Gly Glu Arg Gly Ile                       815      - #           820      - #           825                  - - AAC TTG AGT ACT GGT GGT CAG CGT CCA GAT CA - #G TGT AGA CCC GAG CCC         2788                                                                       Asn Leu Ser Thr Gly Gly Gln Arg Pro Asp Gl - #n Cys Arg Pro Glu Pro                   830          - #       835          - #       840                      - - TCT ACC AGC ACA CCA ATG ATT GTC TTT TTG GA - #T GAC CCT TTC TCG GCT         2836                                                                       Ser Thr Ser Thr Pro Met Ile Val Phe Leu As - #p Asp Pro Phe Ser Ala               845              - #   850              - #   855                          - - CTG GAT GTC CAT CTG AGT GAC CAC CTA ATG CA - #G GCT GGC ATC CTC GAG         2884                                                                       Leu Asp Val His Leu Ser Asp His Leu Met Gl - #n Ala Gly Ile Leu Glu           860                 8 - #65                 8 - #70                 8 -      #75                                                                              - - CTG CTC CGG GAT GAC AAG AGG ACA GTG GTC TT - #G GTG ACC CAC AAG        CTA     2932                                                                    Leu Leu Arg Asp Asp Lys Arg Thr Val Val Le - #u Val Thr His Lys Leu                          880  - #               885  - #               890              - - CAG TAC CTG CCT CAT GCT GAC TGG ATC ATT GC - #T ATG AAG GAT GGC ACC         2980                                                                       Gln Tyr Leu Pro His Ala Asp Trp Ile Ile Al - #a Met Lys Asp Gly Thr                       895      - #           900      - #           905                  - - ATT CAG AGG GAG GGG ACA CTC AAG GAC TTC CA - #G AGG TCT GAG TGC CAG         3028                                                                       Ile Gln Arg Glu Gly Thr Leu Lys Asp Phe Gl - #n Arg Ser Glu Cys Gln                   910          - #       915          - #       920                      - - CTC TTT GAG CAT TGG AAG ACC CTC ATG AAC CG - #G CAG GAC CAA GAG CTG         3076                                                                       Leu Phe Glu His Trp Lys Thr Leu Met Asn Ar - #g Gln Asp Gln Glu Leu               925              - #   930              - #   935                          - - GAG AAG GAG ACA GTC ATG GAG AGA AAA GCC CC - #A GAG CCA TCT CAG GGC         3124                                                                       Glu Lys Glu Thr Val Met Glu Arg Lys Ala Pr - #o Glu Pro Ser Gln Gly           940                 9 - #45                 9 - #50                 9 -      #55                                                                              - - CTG CCC CGT GCC ATG TCC TCA AGA GAT GGC CT - #T CTG CTG GAT GAG        GAT     3172                                                                    Leu Pro Arg Ala Met Ser Ser Arg Asp Gly Le - #u Leu Leu Asp Glu Asp                          960  - #               965  - #               970              - - GAG GAG GAA GAG GAG GCA GCC GAG AGC GAG GA - #A GAT GAC AAC TTA TCC         3220                                                                       Glu Glu Glu Glu Glu Ala Ala Glu Ser Glu Gl - #u Asp Asp Asn Leu Ser                       975      - #           980      - #           985                  - - TCT GTG CTG CAT CAG CGA GCC AAG ATC CCA TG - #G CGA GCC TGC ACC AAG         3268                                                                       Ser Val Leu His Gln Arg Ala Lys Ile Pro Tr - #p Arg Ala Cys Thr Lys                   990          - #       995          - #       1000                     - - TAT TTG TCC TCT GCT GGC ATC CTG CTC CTG TC - #C CTG CTT GTC TTC TCC         3316                                                                       Tyr Leu Ser Ser Ala Gly Ile Leu Leu Leu Se - #r Leu Leu Val Phe Ser               1005             - #   1010              - #  1015                         - - CAG CTG CTC AAG CAC ATG GTC TTG GTG GCC AT - #T GAC TAC TGG CTG GCC         3364                                                                       Gln Leu Leu Lys His Met Val Leu Val Ala Il - #e Asp Tyr Trp Leu Ala           1020                1025 - #                1030 - #               1035        - - AAG TGG ACG GAC AGT GCC CTG GTC CTG AGC CC - #C GCC GCC AGG AAC TGC         3412                                                                       Lys Trp Thr Asp Ser Ala Leu Val Leu Ser Pr - #o Ala Ala Arg Asn Cys                           1040 - #               1045  - #              1050             - - TCC CTC AGC CAG GAA TGT GCC CTG GAC CAA TC - #T GTC TAT GCC ATG GTA         3460                                                                       Ser Leu Ser Gln Glu Cys Ala Leu Asp Gln Se - #r Val Tyr Ala Met Val                       1055     - #           1060      - #          1065                 - - TTC ACC GTG CTC TGC AGC CTG GGT ATC GCG CT - #G TGC CTT GTC ACC TCT         3508                                                                       Phe Thr Val Leu Cys Ser Leu Gly Ile Ala Le - #u Cys Leu Val Thr Ser                   1070         - #       1075          - #      1080                     - - GTC ACT GTG GAG TGG ACG GGA CTG AAG GTG GC - #C AAG AGG CTG CAT CGC         3556                                                                       Val Thr Val Glu Trp Thr Gly Leu Lys Val Al - #a Lys Arg Leu His Arg               1085             - #   1090              - #  1095                         - - AGC CTG CTC AAC CGT ATC ATC CTG GCT CCC AT - #G AGG TTC TTT GAG ACC         3604                                                                       Ser Leu Leu Asn Arg Ile Ile Leu Ala Pro Me - #t Arg Phe Phe Glu Thr           1100                1105 - #                1110 - #               1115        - - ACG CCC CTG GGG AGT ATC CTG AAC AGA TTT TC - #A TCT GAC TGT AAC ACC         3652                                                                       Thr Pro Leu Gly Ser Ile Leu Asn Arg Phe Se - #r Ser Asp Cys Asn Thr                           1120 - #               1125  - #              1130             - - ATT GAC CAG CAT ATC CCG TCC ACG CTG GAG TG - #C CTG AGC AGA TCC ACC         3700                                                                       Ile Asp Gln His Ile Pro Ser Thr Leu Glu Cy - #s Leu Ser Arg Ser Thr                       1135     - #           1140      - #          1145                 - - TTA CTC TGT GTC TCC GCC CTG GCT GTC ATC TC - #C TAC GTC ACG CCT GTG         3748                                                                       Leu Leu Cys Val Ser Ala Leu Ala Val Ile Se - #r Tyr Val Thr Pro Val                   1150         - #       1155          - #      1160                     - - TTC CTA GTG GCC CTC TTA CCC CTC GCC GTC GT - #G TGC TAC TTC ATC CAG         3796                                                                       Phe Leu Val Ala Leu Leu Pro Leu Ala Val Va - #l Cys Tyr Phe Ile Gln               1165             - #   1170              - #  1175                         - - AAG TAC TTC CGA GTG GCG TCC AGG GAC CTG CA - #G CAG CTG GAC GAC ACA         3844                                                                       Lys Tyr Phe Arg Val Ala Ser Arg Asp Leu Gl - #n Gln Leu Asp Asp Thr           1180                1185 - #                1190 - #               1195        - - ACA CAG CTC CCT CTG CTC TCA CAC TTT GCT GA - #A ACT GTG GAA GGA CTC         3892                                                                       Thr Gln Leu Pro Leu Leu Ser His Phe Ala Gl - #u Thr Val Glu Gly Leu                           1200 - #               1205  - #              1210             - - ACC ACC ATC CGT GCC TTC AGG TAC GAG GCC CG - #G TTC CAG CAG AAG CTC         3940                                                                       Thr Thr Ile Arg Ala Phe Arg Tyr Glu Ala Ar - #g Phe Gln Gln Lys Leu                       1215     - #           1220      - #          1225                 - - CTA GAG TAC ACC GAC TCC AAC AAC ATT GCC TC - #T CTC TTC CTC ACA GCA         3988                                                                       Leu Glu Tyr Thr Asp Ser Asn Asn Ile Ala Se - #r Leu Phe Leu Thr Ala                   1230         - #       1235          - #      1240                     - - GCC AAC AGG TGG CTG GAA GTC CGC ATG GAG TA - #C ATC GGA GCA TGC GTG         4036                                                                       Ala Asn Arg Trp Leu Glu Val Arg Met Glu Ty - #r Ile Gly Ala Cys Val               1245             - #   1250              - #  1255                         - - GTA CTC ATC GCC GCT GCC ACC TCC ATC TCC AA - #C TCC CTA CAC AGG GAG         4084                                                                       Val Leu Ile Ala Ala Ala Thr Ser Ile Ser As - #n Ser Leu His Arg Glu           1260                1265 - #                1270 - #               1275        - - CTC TCA GCC GGC CTA GTA GGC CTG GGC CTC AC - #C TAT GCC TTG ATG GTC         4132                                                                       Leu Ser Ala Gly Leu Val Gly Leu Gly Leu Th - #r Tyr Ala Leu Met Val                           1280 - #               1285  - #              1290             - - TCC AAC TAC CTC AAC TGG ATG GTG AGG AAC CT - #G GCA GAC ATG GAG ATC         4180                                                                       Ser Asn Tyr Leu Asn Trp Met Val Arg Asn Le - #u Ala Asp Met Glu Ile                       1295     - #           1300      - #          1305                 - - CAA CTG GGA GCT GTG AAG GGT ATC CAC ACA CT - #C CTG AAA ACT GAG GCA         4228                                                                       Gln Leu Gly Ala Val Lys Gly Ile His Thr Le - #u Leu Lys Thr Glu Ala                   1310         - #       1315          - #      1320                     - - GAG AGC TAT GAG GGG CTC CTG GCA CCA TCG CT - #G ATC CCC AAG AAC TGG         4276                                                                       Glu Ser Tyr Glu Gly Leu Leu Ala Pro Ser Le - #u Ile Pro Lys Asn Trp               1325             - #   1330              - #  1335                         - - CCA GAC CAA GGG AAG ATC CAA ATT CAA AAC CT - #G AGT GTA CGC TAT GAC         4324                                                                       Pro Asp Gln Gly Lys Ile Gln Ile Gln Asn Le - #u Ser Val Arg Tyr Asp           1340                1345 - #                1350 - #               1355        - - AGC TCC CTG AAG CCC GTG CTG AAG CAC GTC AA - #C GCC CTC ATC TCC CCA         4372                                                                       Ser Ser Leu Lys Pro Val Leu Lys His Val As - #n Ala Leu Ile Ser Pro                           1360 - #               1365  - #              1370             - - GGA CAG AAG ATT GGG ATC TGC GGC CGC ACA GG - #C AGT GGA AAA TCC TCC         4420                                                                       Gly Gln Lys Ile Gly Ile Cys Gly Arg Thr Gl - #y Ser Gly Lys Ser Ser                       1375     - #           1380      - #          1385                 - - TTC TCT CTC GCC TTT TTC CGA ATG GTG GAT AT - #G TTT GAA GGG CGT ATC         4468                                                                       Phe Ser Leu Ala Phe Phe Arg Met Val Asp Me - #t Phe Glu Gly Arg Ile                   1390         - #       1395          - #      1400                     - - ATC ATC GAT GGC ATT GAC ATC GCC AAG CTG CC - #G CTG CAC ACG CTC GGC         4516                                                                       Ile Ile Asp Gly Ile Asp Ile Ala Lys Leu Pr - #o Leu His Thr Leu Gly               1405             - #   1410              - #  1415                         - - TCA CGC CTG TCT ATC ATC CTA CAG GAC CCT GT - #T CTC TTC AGT GGT ACC         4564                                                                       Ser Arg Leu Ser Ile Ile Leu Gln Asp Pro Va - #l Leu Phe Ser Gly Thr           1420                1425 - #                1430 - #               1435        - - ATC AGA TTC AAC CTG GAC CCA GAG AAG AAA TG - #C TCA GAC AGC ACG CTG         4612                                                                       Ile Arg Phe Asn Leu Asp Pro Glu Lys Lys Cy - #s Ser Asp Ser Thr Leu                           1440 - #               1445  - #              1450             - - TGG GAG GCT CTG GAG ATC GCT CAG CTG AAG CT - #G GTG GTG AAG GCC CTG         4660                                                                       Trp Glu Ala Leu Glu Ile Ala Gln Leu Lys Le - #u Val Val Lys Ala Leu                       1455     - #           1460      - #          1465                 - - CCA GGA GGC CTG GAT GCC ATC ATC ACG GAA GG - #A GGG GAG AAT TTT AGC         4708                                                                       Pro Gly Gly Leu Asp Ala Ile Ile Thr Glu Gl - #y Gly Glu Asn Phe Ser                   1470         - #       1475          - #      1480                     - - CAG GGC CAG AGG CAG CTG TTC TGC CTG GCC CG - #G GCC TTT GTG AGG AAG         4756                                                                       Gln Gly Gln Arg Gln Leu Phe Cys Leu Ala Ar - #g Ala Phe Val Arg Lys               1485             - #   1490              - #  1495                         - - ACC AGC ATC TTC ATC ATG GAT GAA GCA ACT GC - #C TCC ATC GAC ATG GCT         4804                                                                       Thr Ser Ile Phe Ile Met Asp Glu Ala Thr Al - #a Ser Ile Asp Met Ala           1500                1505 - #                1510 - #               1515        - - ACG GAA AAT ATC CTC CAG AAG GTG GTG ATG AC - #A GCC TTC GCA GAC CGC         4852                                                                       Thr Glu Asn Ile Leu Gln Lys Val Val Met Th - #r Ala Phe Ala Asp Arg                           1520 - #               1525  - #              1530             - - ACC GTG GTC ACC ATC GCG CAC CGC GTG CAC AC - #C ATC CTG AGT GCA GAC         4900                                                                       Thr Val Val Thr Ile Ala His Arg Val His Th - #r Ile Leu Ser Ala Asp                       1535     - #           1540      - #          1545                 - - CTA GTG ATG GTC CTG AAG AGG GGC GCG ATC CT - #G GAG TTC GAC AAG CCG         4948                                                                       Leu Val Met Val Leu Lys Arg Gly Ala Ile Le - #u Glu Phe Asp Lys Pro                   1550         - #       1555          - #      1560                     - - GAA AAG CTT CTC AGC CAG AAG GAC AGC GTC TT - #T GCC TCC TTT GTC CGC         4996                                                                       Glu Lys Leu Leu Ser Gln Lys Asp Ser Val Ph - #e Ala Ser Phe Val Arg               1565             - #   1570              - #  1575                         - - GCG GAC AA ATGACCAGCC AGCGCCAAAG TGCCACCCCA CACCTCACCT - # GCTTGCCAT    G   5054                                                                       Ala Asp                                                                       1580                                                                           - - GATTTCTTAC TGTAAATCAC TTGTAAATAA AGAAACTAAT TCTTTGCTAA AA - #AAAA           5110                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:6:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1581 amino - #acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                               - - Met Pro Leu Ala Phe Cys Gly Thr Glu Asn Hi - #s Ser Ala Ala Tyr Arg        1               5 - #                 10 - #                 15              - - Val Asp Gln Gly Val Leu Asn Asn Gly Cys Ph - #e Val Asp Ala Leu Asn                   20     - #             25     - #             30                  - - Val Val Pro His Val Phe Leu Leu Phe Ile Th - #r Phe Pro Ile Leu Phe               35         - #         40         - #         45                      - - Ile Gly Trp Gly Ser Gln Ser Ser Lys Val Hi - #s Ile His His Ser Thr           50             - #     55             - #     60                          - - Trp Leu His Phe Pro Gly His Asn Leu Arg Tr - #p Ile Leu Thr Phe Ile       65                 - # 70                 - # 75                 - # 80       - - Leu Leu Phe Val Leu Val Cys Glu Ile Ala Gl - #u Gly Ile Leu Ser Asp                       85 - #                 90 - #                 95              - - Gly Val Thr Glu Ser Arg His Leu His Leu Ty - #r Met Pro Ala Gly Met                  100      - #           105      - #           110                  - - Ala Phe Met Ala Ala Ile Thr Ser Val Val Ty - #r Tyr His Asn Ile Glu              115          - #       120          - #       125                      - - Thr Ser Asn Phe Pro Lys Leu Leu Ile Ala Le - #u Leu Ile Tyr Trp Thr          130              - #   135              - #   140                          - - Leu Ala Phe Ile Thr Lys Thr Ile Lys Phe Va - #l Lys Phe Tyr Asp His      145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - Ala Ile Gly Phe Ser Gln Leu Arg Phe Cys Le - #u Thr Gly Leu Leu        Val                                                                                             165  - #               170  - #               175             - - Ile Leu Tyr Gly Met Leu Leu Leu Val Glu Va - #l Asn Val Ile Arg Val                  180      - #           185      - #           190                  - - Arg Arg Tyr Val Phe Phe Lys Thr Pro Arg Gl - #u Val Lys Pro Pro Glu              195          - #       200          - #       205                      - - Asp Leu Gln Asp Leu Gly Val Arg Phe Leu Gl - #n Pro Phe Val Asn Leu          210              - #   215              - #   220                          - - Leu Ser Lys Gly Thr Tyr Trp Trp Met Asn Al - #a Phe Ile Lys Thr Ala      225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - His Lys Lys Pro Ile Asp Leu Arg Ala Ile Gl - #y Lys Leu Pro Ile        Ala                                                                                             245  - #               250  - #               255             - - Met Arg Ala Leu Thr Asn Tyr Gln Arg Leu Cy - #s Leu Ala Phe Asp Ala                  260      - #           265      - #           270                  - - Gln Ala Arg Lys Asp Thr Gln Ser Gln Gln Gl - #y Ala Arg Ala Ile Trp              275          - #       280          - #       285                      - - Arg Ala Leu Cys His Ala Phe Gly Arg Arg Le - #u Val Leu Ser Ser Thr          290              - #   295              - #   300                          - - Phe Arg Ile Leu Ala Asp Leu Leu Gly Phe Al - #a Gly Pro Leu Cys Ile      305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - Phe Gly Ile Val Asp His Leu Gly Lys Glu As - #n His Val Phe Gln        Pro                                                                                             325  - #               330  - #               335             - - Lys Thr Gln Phe Leu Gly Val Tyr Phe Val Se - #r Ser Gln Glu Phe Leu                  340      - #           345      - #           350                  - - Gly Asn Ala Tyr Val Leu Ala Val Leu Leu Ph - #e Leu Ala Leu Leu Leu              355          - #       360          - #       365                      - - Gln Arg Thr Phe Leu Gln Ala Ser Tyr Tyr Va - #l Ala Ile Glu Thr Gly          370              - #   375              - #   380                          - - Ile Asn Leu Arg Gly Ala Ile Gln Thr Lys Il - #e Tyr Asn Lys Ile Met      385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - His Leu Ser Thr Ser Asn Leu Ser Met Gly Gl - #u Met Thr Ala Gly        Gln                                                                                             405  - #               410  - #               415             - - Ile Cys Asn Leu Val Ala Ile Asp Thr Asn Gl - #n Leu Met Trp Phe Phe                  420      - #           425      - #           430                  - - Phe Leu Cys Pro Asn Leu Trp Ala Met Pro Va - #l Gln Ile Ile Val Gly              435          - #       440          - #       445                      - - Val Ile Leu Leu Tyr Tyr Ile Leu Gly Val Se - #r Ala Leu Ile Gly Ala          450              - #   455              - #   460                          - - Ala Val Ile Ile Leu Leu Ala Pro Val Gln Ty - #r Phe Val Ala Thr Lys      465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - Leu Ser Gln Ala Gln Arg Thr Thr Leu Glu Ty - #r Ser Asn Glu Arg        Leu                                                                                             485  - #               490  - #               495             - - Lys Gln Thr Asn Glu Met Leu Arg Gly Ile Ly - #s Leu Leu Lys Leu Tyr                  500      - #           505      - #           510                  - - Ala Trp Glu Asn Ile Phe Cys Ser Arg Val Gl - #u Lys Thr Arg Arg Lys              515          - #       520          - #       525                      - - Glu Met Thr Ser Leu Arg Ala Phe Ala Val Ty - #r Thr Ser Ile Ser Ile          530              - #   535              - #   540                          - - Phe Met Asn Thr Ala Ile Pro Ile Ala Ala Va - #l Leu Ile Thr Phe Val      545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - Gly His Val Ser Phe Phe Lys Glu Ser Asp Ph - #e Ser Pro Ser Val        Ala                                                                                             565  - #               570  - #               575             - - Phe Ala Ser Leu Ser Leu Phe His Ile Leu Va - #l Thr Pro Leu Phe Leu                  580      - #           585      - #           590                  - - Leu Ser Ser Val Val Arg Ser Thr Val Lys Al - #a Leu Val Ser Val Gln              595          - #       600          - #       605                      - - Lys Leu Ser Glu Phe Leu Ser Ser Ala Glu Il - #e Arg Glu Glu Gln Cys          610              - #   615              - #   620                          - - Ala Pro Arg Glu Pro Ala Pro Gln Gly Gln Al - #a Gly Lys Tyr Gln Ala      625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - Val Pro Leu Lys Val Val Asn Arg Lys Arg Pr - #o Ala Arg Glu Glu        Val                                                                                             645  - #               650  - #               655             - - Arg Asp Leu Leu Gly Pro Leu Gln Arg Leu Th - #r Pro Ser Thr Asp Gly                  660      - #           665      - #           670                  - - Asp Ala Asp Asn Phe Cys Val Gln Ile Ile Gl - #y Gly Phe Phe Thr Trp              675          - #       680          - #       685                      - - Thr Pro Asp Gly Ile Pro Thr Leu Ser Asn Il - #e Thr Ile Arg Ile Pro          690              - #   695              - #   700                          - - Arg Gly Gln Leu Thr Met Ile Val Gly Gln Va - #l Gly Cys Gly Lys Ser      705                 7 - #10                 7 - #15                 7 -      #20                                                                              - - Ser Leu Leu Leu Ala Thr Leu Gly Glu Met Gl - #n Lys Val Ser Gly        Ala                                                                                             725  - #               730  - #               735             - - Val Phe Trp Asn Ser Leu Pro Asp Ser Glu Gl - #y Arg Arg Pro Gln Gln                  740      - #           745      - #           750                  - - Pro Arg Ala Gly Asp Ser Gly Arg Phe Gly Cy - #s Gln Glu Gln Arg Pro              755          - #       760          - #       765                      - - Cys Gly Tyr Ala Ser Gln Lys Pro Trp Leu Le - #u Asn Ala Thr Val Glu          770              - #   775              - #   780                          - - Glu Asn Ile Thr Phe Glu Ser Pro Phe Asn Ly - #s Gln Arg Tyr Lys Met      785                 7 - #90                 7 - #95                 8 -      #00                                                                              - - Val Ile Glu Ala Cys Ser Leu Gln Pro Asp Il - #e Asp Ile Leu Pro        His                                                                                             805  - #               810  - #               815             - - Gly Asp Gln Thr Gln Ile Gly Glu Arg Gly Il - #e Asn Leu Ser Thr Gly                  820      - #           825      - #           830                  - - Gly Gln Arg Pro Asp Gln Cys Arg Pro Glu Pr - #o Ser Thr Ser Thr Pro              835          - #       840          - #       845                      - - Met Ile Val Phe Leu Asp Asp Pro Phe Ser Al - #a Leu Asp Val His Leu          850              - #   855              - #   860                          - - Ser Asp His Leu Met Gln Ala Gly Ile Leu Gl - #u Leu Leu Arg Asp Asp      865                 8 - #70                 8 - #75                 8 -      #80                                                                              - - Lys Arg Thr Val Val Leu Val Thr His Lys Le - #u Gln Tyr Leu Pro        His                                                                                             885  - #               890  - #               895             - - Ala Asp Trp Ile Ile Ala Met Lys Asp Gly Th - #r Ile Gln Arg Glu Gly                  900      - #           905      - #           910                  - - Thr Leu Lys Asp Phe Gln Arg Ser Glu Cys Gl - #n Leu Phe Glu His Trp              915          - #       920          - #       925                      - - Lys Thr Leu Met Asn Arg Gln Asp Gln Glu Le - #u Glu Lys Glu Thr Val          930              - #   935              - #   940                          - - Met Glu Arg Lys Ala Pro Glu Pro Ser Gln Gl - #y Leu Pro Arg Ala Met      945                 9 - #50                 9 - #55                 9 -      #60                                                                              - - Ser Ser Arg Asp Gly Leu Leu Leu Asp Glu As - #p Glu Glu Glu Glu        Glu                                                                                             965  - #               970  - #               975             - - Ala Ala Glu Ser Glu Glu Asp Asp Asn Leu Se - #r Ser Val Leu His Gln                  980      - #           985      - #           990                  - - Arg Ala Lys Ile Pro Trp Arg Ala Cys Thr Ly - #s Tyr Leu Ser Ser Ala              995          - #       1000          - #      1005                     - - Gly Ile Leu Leu Leu Ser Leu Leu Val Phe Se - #r Gln Leu Leu Lys His          1010             - #   1015              - #  1020                         - - Met Val Leu Val Ala Ile Asp Tyr Trp Leu Al - #a Lys Trp Thr Asp Ser      1025                1030 - #                1035 - #               1040        - - Ala Leu Val Leu Ser Pro Ala Ala Arg Asn Cy - #s Ser Leu Ser Gln Glu                      1045 - #               1050  - #              1055             - - Cys Ala Leu Asp Gln Ser Val Tyr Ala Met Va - #l Phe Thr Val Leu Cys                  1060     - #           1065      - #          1070                 - - Ser Leu Gly Ile Ala Leu Cys Leu Val Thr Se - #r Val Thr Val Glu Trp              1075         - #       1080          - #      1085                     - - Thr Gly Leu Lys Val Ala Lys Arg Leu His Ar - #g Ser Leu Leu Asn Arg          1090             - #   1095              - #  1100                         - - Ile Ile Leu Ala Pro Met Arg Phe Phe Glu Th - #r Thr Pro Leu Gly Ser      1105                1110 - #                1115 - #               1120        - - Ile Leu Asn Arg Phe Ser Ser Asp Cys Asn Th - #r Ile Asp Gln His Ile                      1125 - #               1130  - #              1135             - - Pro Ser Thr Leu Glu Cys Leu Ser Arg Ser Th - #r Leu Leu Cys Val Ser                  1140     - #           1145      - #          1150                 - - Ala Leu Ala Val Ile Ser Tyr Val Thr Pro Va - #l Phe Leu Val Ala Leu              1155         - #       1160          - #      1165                     - - Leu Pro Leu Ala Val Val Cys Tyr Phe Ile Gl - #n Lys Tyr Phe Arg Val          1170             - #   1175              - #  1180                         - - Ala Ser Arg Asp Leu Gln Gln Leu Asp Asp Th - #r Thr Gln Leu Pro Leu      1185                1190 - #                1195 - #               1200        - - Leu Ser His Phe Ala Glu Thr Val Glu Gly Le - #u Thr Thr Ile Arg Ala                      1205 - #               1210  - #              1215             - - Phe Arg Tyr Glu Ala Arg Phe Gln Gln Lys Le - #u Leu Glu Tyr Thr Asp                  1220     - #           1225      - #          1230                 - - Ser Asn Asn Ile Ala Ser Leu Phe Leu Thr Al - #a Ala Asn Arg Trp Leu              1235         - #       1240          - #      1245                     - - Glu Val Arg Met Glu Tyr Ile Gly Ala Cys Va - #l Val Leu Ile Ala Ala          1250             - #   1255              - #  1260                         - - Ala Thr Ser Ile Ser Asn Ser Leu His Arg Gl - #u Leu Ser Ala Gly Leu      1265                1270 - #                1275 - #               1280        - - Val Gly Leu Gly Leu Thr Tyr Ala Leu Met Va - #l Ser Asn Tyr Leu Asn                      1285 - #               1290  - #              1295             - - Trp Met Val Arg Asn Leu Ala Asp Met Glu Il - #e Gln Leu Gly Ala Val                  1300     - #           1305      - #          1310                 - - Lys Gly Ile His Thr Leu Leu Lys Thr Glu Al - #a Glu Ser Tyr Glu Gly              1315         - #       1320          - #      1325                     - - Leu Leu Ala Pro Ser Leu Ile Pro Lys Asn Tr - #p Pro Asp Gln Gly Lys          1330             - #   1335              - #  1340                         - - Ile Gln Ile Gln Asn Leu Ser Val Arg Tyr As - #p Ser Ser Leu Lys Pro      1345                1350 - #                1355 - #               1360        - - Val Leu Lys His Val Asn Ala Leu Ile Ser Pr - #o Gly Gln Lys Ile Gly                      1365 - #               1370  - #              1375             - - Ile Cys Gly Arg Thr Gly Ser Gly Lys Ser Se - #r Phe Ser Leu Ala Phe                  1380     - #           1385      - #          1390                 - - Phe Arg Met Val Asp Met Phe Glu Gly Arg Il - #e Ile Ile Asp Gly Ile              1395         - #       1400          - #      1405                     - - Asp Ile Ala Lys Leu Pro Leu His Thr Leu Gl - #y Ser Arg Leu Ser Ile          1410             - #   1415              - #  1420                         - - Ile Leu Gln Asp Pro Val Leu Phe Ser Gly Th - #r Ile Arg Phe Asn Leu      1425                1430 - #                1435 - #               1440        - - Asp Pro Glu Lys Lys Cys Ser Asp Ser Thr Le - #u Trp Glu Ala Leu Glu                      1445 - #               1450  - #              1455             - - Ile Ala Gln Leu Lys Leu Val Val Lys Ala Le - #u Pro Gly Gly Leu Asp                  1460     - #           1465      - #          1470                 - - Ala Ile Ile Thr Glu Gly Gly Glu Asn Phe Se - #r Gln Gly Gln Arg Gln              1475         - #       1480          - #      1485                     - - Leu Phe Cys Leu Ala Arg Ala Phe Val Arg Ly - #s Thr Ser Ile Phe Ile          1490             - #   1495              - #  1500                         - - Met Asp Glu Ala Thr Ala Ser Ile Asp Met Al - #a Thr Glu Asn Ile Leu      1505                1510 - #                1515 - #               1520        - - Gln Lys Val Val Met Thr Ala Phe Ala Asp Ar - #g Thr Val Val Thr Ile                      1525 - #               1530  - #              1535             - - Ala His Arg Val His Thr Ile Leu Ser Ala As - #p Leu Val Met Val Leu                  1540     - #           1545      - #          1550                 - - Lys Arg Gly Ala Ile Leu Glu Phe Asp Lys Pr - #o Glu Lys Leu Leu Ser              1555         - #       1560          - #      1565                     - - Gln Lys Asp Ser Val Phe Ala Ser Phe Val Ar - #g Ala Asp                      1570             - #   1575              - #  1580                         - -  - - (2) INFORMATION FOR SEQ ID NO:7:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4877 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                               - - AGCCGAGCCC GTGCGCGCGC CGCCATGCCC TTGGCCTTCT GCGGTACCGA GA -             #ACCACTCG     60                                                                 - - GCCGCCTACC GGGTGGACCA GGGCGTCCTC AACAACGGCT GCTTCGTGGA CG -            #CGCTCAAC    120                                                                 - - GTGGTGCCGC ACGTTTTCCT GCTCTTCATC ACCTTCCCCA TCCTCTTCAT CG -            #GATGGGGC    180                                                                 - - AGCCAGAGCT CCAAGGTGCA CATCCACCAC AGCACCTGGC TGCACTTTCC AG -            #GGCACAAC    240                                                                 - - CTGCGCTGGA TCCTTACCTT CATTTTGCTC TTCGTCCTTG TGTGTGAGAT CG -            #CTGAGGGC    300                                                                 - - ATCCTGTCTG ATGGGGTGAC AGAATCCCGC CACCTCCACC TGTACATGCC AG -            #CCGGGATG    360                                                                 - - GCGTTCATGG CTGCCATCAC CTCTGTAGTC TACTATCATA ACATCGAGAC CT -            #CCAACTTC    420                                                                 - - CCCAAGCTTT TGATCGCTCT GCTCATCTAT TGGACCCTGG CCTTCATCAC GA -            #AGACCATC    480                                                                 - - AAGTTTGTCA AGTTCTATGA CCACGCCATC GGCTTCTCCC AGCTGCGCTT CT -            #GCCTCACG    540                                                                 - - GGGCTTCTGG TGATCCTGTA TGGGATGTTG CTGCTTGTGG AGGTCAACGT CA -            #TCAGAGTG    600                                                                 - - AGGAGGTACA TCTTCTTCAA GACGCCACGG GAGGTGAAGC CCCCTGAGGA CC -            #TGCAGGAC    660                                                                 - - CTGGGTGTGC GCTTTCTGCA GCCCTTCGTT AACCTGCTGT CAAAGGGGAC CT -            #ATTGGTGG    720                                                                 - - ATGAATGCCT TCATCAAGAC GGCCCACAAG AAGCCCATCG ACCTGCGGGC CA -            #TCGCGAAG    780                                                                 - - CTGCCCATCG CCATGAGAGC CCTCACCAAC TATCAGCGCC TCTGCGTGGC CT -            #TCGATGCT    840                                                                 - - CAGGCGCGGA AGGACACACA GAGCCCACAG GGTGCCCGGG CCATCTGGAG GG -            #CTCTATGC    900                                                                 - - CATGCCTTTG GGAGACGCCT GATCCTCAGC AGCACATTCC GCATCCTGGC TG -            #ACCTGTTG    960                                                                 - - GGCTTCGCTG GACCACTCTG CATCTTTGGG ATCGTGGACC ACCTGGGGAA GG -            #AGAACCAC   1020                                                                 - - GTCTTCCAGC CCAAGACACA GTTTCTCGGG GTTTACTTCG TCTCTTCTCA AG -            #AGTTCCTT   1080                                                                 - - GGCAATGCCT ACGTCTTGGC CGTGCTTCTG TTCCTTGCCC TGCTACTGCA AA -            #GGACATTC   1140                                                                 - - CTGCAAGCCT CATACTACGT CGCCATTGAA ACTGGAATTA ACCTGAGAGG AG -            #CAATCCAG   1200                                                                 - - ACCAAGATTT ACAATAAAAT CATGCACATG TCCACCTCCA ACCTGTCAAT GG -            #GGGAAATG   1260                                                                 - - ACTGCTGGGC AGATCTGCAA CCTGGTGGCC ATCGACACAA ACCAGCTCAT GT -            #GGTTCTTC   1320                                                                 - - TTTCTGTGCC CAAACCTCTG GACGATGCCA GTACAGATCA TTGTGGGCGT GA -            #TCCTTCTC   1380                                                                 - - TACTACATCC TTGGGGTCAG TGCCTTGATT GGAGCAGCTG TCATCATTCT GC -            #TGGCTCCT   1440                                                                 - - GTACAGTACT TTGTGGCCAC CAAGCTCTCC CAGGCACAGC GGACGACCTT GG -            #AGCACTCC   1500                                                                 - - AACGAGAGGC TGAAGCAGAC CAACGAGATG CTCCGGGGCA TGAAGCTGCT CA -            #AACTGTAT   1560                                                                 - - GCGTGGGAGA GCATCTTCTG CTCCAGGGTG GAGGTGACTC GCAGGAAGGA GA -            #TGACCAGC   1620                                                                 - - CTGAGGGCGT TTGCTGTCTA CACTTCCATC TCCATCTTCA TGAACACAGC CA -            #TCCCCATT   1680                                                                 - - GCTGCCGTCC TCATCACCTT CGTGGGCCAC GTCAGCTTCT TCAAAGAGTC GG -            #ACTTGTCA   1740                                                                 - - CCCTCGGTGG CCTTTGCCTC CCTCTCTCTC TTCCACATCC TGGTCACTCC AC -            #TGTTCCTG   1800                                                                 - - CTGTCTAGCG TGGTTCGGTC CACTGTCAAA GCCCTGGTGA GCGTGCAAAA AC -            #TGAGCGAG   1860                                                                 - - TTCCTGTCTA GTGCAGAGAT CCGTGAGGAG CAGTGTGCCC CCCGAGAGCC TG -            #CACCCCAA   1920                                                                 - - GGCCAAGCCG GCAAGTACCA GGCAGTGCCC CTCAAGGTTG TGAACCGCAA AC -            #GCCCAGCC   1980                                                                 - - CGGGAAGAGG TCCGGGACCT CCTGGGCCCA CTGCAGAGGC TGGCCCCTAG CA -            #TGGACGGG   2040                                                                 - - GATGCTGACA ACTTCTGTGT CCAGATCATC GGAGGCTTCT TCACCTGGAC CC -            #CTGATGGA   2100                                                                 - - ATCCCCACTC TGTCCAACAT CACCATCCGT ATTCCCCGAG GTCAGCTAAC CA -            #TGATTGTG   2160                                                                 - - GGGCAGGTGG GCTGCGGCAA GTCCTCGCTC CTCCTCGCCA CCCTGGGGGA GA -            #TGCAGAAG   2220                                                                 - - GTGTCGGGGG CCGTCTTCTG GAACAGCAAC CTTCCGGACA GCGAGGGGAG AG -            #GACCCCAG   2280                                                                 - - CAGCCCAGAG CGGGAGACAG CAGCTGGCTC GGATATCAGG AGCAGAGGCC CC -            #GTGGCTAC   2340                                                                 - - GCATCTCAGA AACCATGGCT GCTAAACGCC ACCGTGGAAG AGAACATCAC CT -            #TCGAGAGT   2400                                                                 - - CCCTTCAATC CGCAGCGGTA CAAGATGGTC ATCGAAGCCT GCTCCCTGCA GC -            #CGGACATA   2460                                                                 - - GACATCCTGC CCCACGGAGA CCAGACTCAG ATTGGGGAAC GGGGCATCAA CC -            #TGTCTGGT   2520                                                                 - - GGTCAGCGTC CAGATCAGTG TGGTCCAGAG CCCTCTACCA GCAGACCAAT GT -            #TCGTCTTC   2580                                                                 - - TTGGATGACC CCTTCTCAGC TTTGGATGTC CATCTGAGTG ACCACCTGAT GC -            #AGGCCGGC   2640                                                                 - - ATCCTTGAGC TGCTCCGGGA TGACAAGAGG ACAGTGGTCT TGGTGACCCA CA -            #AGCTACAG   2700                                                                 - - TATCTGCCTC ATGCAGACTG GATCATTGCC ATGAAGGATG GGACCATTCA GA -            #GGGAAGGG   2760                                                                 - - ACGCTCAAGG ACTTCCAGAG GTCCGAGTGC CAGCTCTTTG AGCACTGGAA GA -            #CCCTCATG   2820                                                                 - - AACCGGCAGG ACCAAGAGCT GGAGAAGGAG ACAGTCATGG AGAGGAAAGC CT -            #CAGAGCCA   2880                                                                 - - TCTCAGGGCC TGCCCCGTGC CATGTCCTCC AGAGACGGCC TTCTGCTGGA TG -            #AGGAAGAG   2940                                                                 - - GAGGAAGAGG AGGCAGCCGA AAGCGAGGAA GATGACAACT TATCTTCAGT GC -            #TGCATCAG   3000                                                                 - - CGAGCTAAGA TCCCCTGGCG AGCCTGCACT AAGTATCTGT CCTCTGCTGG CA -            #TTCTGCTC   3060                                                                 - - CTGTCCCTGC TTGTCTTCTC CCAGCTGCTC AAGCACATGG TCTTGGTGGC CA -            #TTGATTAT   3120                                                                 - - TGGCTGGCCA AGTGGACGGA CAGTGCCCTG GTCCTGAGCC CCGCTGCCAG GA -            #ACTGTTCG   3180                                                                 - - CTCAGCCAGG AATGTGACCT GGACCAGTCT GTCTATGCCA TGGTATTCAC CT -            #TGCTCTGC   3240                                                                 - - AGCCTGGGTA TCGTGCTGTG CCTGGTCACC TCTGTCACTG TGGAGTGGAC GG -            #GACTGAAG   3300                                                                 - - GTGGCCAAGA GGCTACACCG CAGCCTGCTC AACCGCATCA TCCTGGCCCC CA -            #TGAGGTTC   3360                                                                 - - TTTGAGACCA CACCCCTCGG GAGTATCCTG AACAGATTTT CATCCGACTG TA -            #ACACCATT   3420                                                                 - - GACCAGCACA TCCCATCCAC GCTGGAGTGT CTGAGCCGGT CCACCCTGCT GT -            #GTGTCTCC   3480                                                                 - - GCCCTGACTG TCATCTCCTA TGTCACACCC GTGTTCCTCG TGGCCCTCTT AC -            #CCCTAGCT   3540                                                                 - - GTTGTGTGCT ACTTCATTCA GAAGTACTTC CGAGTGGCAT CCAGGGACCT GC -            #AGCAGCTG   3600                                                                 - - GACGACACGA CGCAGCTCCC GCTCGTCTCA CACTTTGCTG AAACTGTGGA GG -            #GACTCACC   3660                                                                 - - ACCATCCGTG CCTTCAGGTA CGAGGCCCGG TTCCAGCAGA AGCTTCTAGA AT -            #ATACCGAC   3720                                                                 - - TCCAACAACA TCGCCTCCCT CTTCCTCACG GCAGCCAACA GATGGCTGGA AG -            #TCTGCATG   3780                                                                 - - GAGTACATCG GAGCGTGCGT GGTACTCATT GCGGCTGCCA CCTCCATCTC CA -            #ACTCCCTG   3840                                                                 - - CACAGGGAAC TTTCTGCTGG CCTGGTGGGC CTGGGCCTCA CCTATGCCTT GA -            #TGGTCTCC   3900                                                                 - - AACTACCTCA ACTGGATGGT GAGGAACCTG GCGGACATGG AGATCCAGCT GG -            #GGGCTGTG   3960                                                                 - - AAGAGGATCC ACGCACTCCT GAAAACCGAG GCGGAGAGCT ATGAGGGGCT CC -            #TGGCGCCG   4020                                                                 - - TCGTTGATCC CCAAGAACTG GCCAGACCAA GGGAAGATCC AAATTCAGAA CC -            #TGAGCGTG   4080                                                                 - - CGCTATGACA GCTCCCTGAA GCCAGTGCTG AAGCATGTCA ACACCCTCAT CT -            #CCCCGGGG   4140                                                                 - - CAGAAGATCG GGATCTGCGG CCGCACAGGC AGCGGGAAGT CCTCCTTCTC CC -            #TGGCCTTT   4200                                                                 - - TTCCGAATGG TGGACATGTT TGAAGGACGC ATCATCATTG ATGGCATCGA CA -            #TCGCCAAG   4260                                                                 - - CTGCCACTTC ACACGCTGCG CTCACGCCTG TCCATCATCC TACAGGACCC CG -            #TCCTCTTC   4320                                                                 - - AGCGGCACGA TCAGATTCAA CCTGGACCCC GAGAAGAAAT GCTCAGACAG CA -            #CACTGTGG   4380                                                                 - - GAGGCCCTGG AGATCGCCCA GCTGAAGCTG GTAGTGAAGG CACTGCCAGG AG -            #GCCTAGAT   4440                                                                 - - GCCATCATCA CAGAAGGAGG GGAGAATTTT AGCCAGGGCC AGAGGCAGCT GT -            #TCTGCCTG   4500                                                                 - - GCCCGGGCCT TCGTGAGGAA GACCAGCATC TTCATCATGG ATGAAGCAAC CG -            #CCTCCATC   4560                                                                 - - GACATGGCTA CGGAGAACAT CCTCCAGAAG GTGGTGATGA CAGCCTTCGC AG -            #ACCGCACG   4620                                                                 - - GTGGTCACCA TCGCGCATCG TGTGCACACC ATCCTGAGTG CAGACCTGGT GA -            #TGGTCCTC   4680                                                                 - - AAGAGGGGTG CTATCCTGGA GTTTGACAAG CCAGAGACGC TCCTCAGCCA GA -            #AGGACAGC   4740                                                                 - - GTGTTCGCCT CCTTTGTCCG TGCGGACAAG TGACTTACCG GAGCCAAAGT GC -            #CACCCCGC   4800                                                                 - - GCCTCGCTTG CTTGCCTAGG ATTTCTAACT GCAAATCACT TGTAAATAAA TT -            #AATTCTTT   4860                                                                 - - GCTAAAAAAA AAAAAAA             - #                  - #                      - # 4877                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:8:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4877 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 25..4770                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                               - - AGCCGAGCCC GTGCGCGCGC CGCC ATG CCC TTG GCC TTC T - #GC GGT ACC GAG            51                                                                                         - #         Met Pro Leu Ala Phe - #Cys Gly Thr Glu                            - #           1       - #        5                           - - AAC CAC TCG GCC GCC TAC CGG GTG GAC CAG GG - #C GTC CTC AAC AAC GGC           99                                                                       Asn His Ser Ala Ala Tyr Arg Val Asp Gln Gl - #y Val Leu Asn Asn Gly            10                 - # 15                 - # 20                 - # 25       - - TGC TTC GTG GAC GCG CTC AAC GTG GTG CCG CA - #C GTT TTC CTG CTC TTC          147                                                                       Cys Phe Val Asp Ala Leu Asn Val Val Pro Hi - #s Val Phe Leu Leu Phe                            30 - #                 35 - #                 40              - - ATC ACC TTC CCC ATC CTC TTC ATC GGA TGG GG - #C AGC CAG AGC TCC AAG          195                                                                       Ile Thr Phe Pro Ile Leu Phe Ile Gly Trp Gl - #y Ser Gln Ser Ser Lys                        45     - #             50     - #             55                  - - GTG CAC ATC CAC CAC AGC ACC TGG CTG CAC TT - #T CCA GGG CAC AAC CTG          243                                                                       Val His Ile His His Ser Thr Trp Leu His Ph - #e Pro Gly His Asn Leu                    60         - #         65         - #         70                      - - CGC TGG ATC CTT ACC TTC ATT TTG CTC TTC GT - #C CTT GTG TGT GAG ATC          291                                                                       Arg Trp Ile Leu Thr Phe Ile Leu Leu Phe Va - #l Leu Val Cys Glu Ile                75             - #     80             - #     85                          - - GCT GAG GGC ATC CTG TCT GAT GGG GTG ACA GA - #A TCC CGC CAC CTC CAC          339                                                                       Ala Glu Gly Ile Leu Ser Asp Gly Val Thr Gl - #u Ser Arg His Leu His            90                 - # 95                 - #100                 - #105       - - CTG TAC ATG CCA GCC GGG ATG GCG TTC ATG GC - #T GCC ATC ACC TCT GTA          387                                                                       Leu Tyr Met Pro Ala Gly Met Ala Phe Met Al - #a Ala Ile Thr Ser Val                           110  - #               115  - #               120              - - GTC TAC TAT CAT AAC ATC GAG ACC TCC AAC TT - #C CCC AAG CTT TTG ATC          435                                                                       Val Tyr Tyr His Asn Ile Glu Thr Ser Asn Ph - #e Pro Lys Leu Leu Ile                       125      - #           130      - #           135                  - - GCT CTG CTC ATC TAT TGG ACC CTG GCC TTC AT - #C ACG AAG ACC ATC AAG          483                                                                       Ala Leu Leu Ile Tyr Trp Thr Leu Ala Phe Il - #e Thr Lys Thr Ile Lys                   140          - #       145          - #       150                      - - TTT GTC AAG TTC TAT GAC CAC GCC ATC GGC TT - #C TCC CAG CTG CGC TTC          531                                                                       Phe Val Lys Phe Tyr Asp His Ala Ile Gly Ph - #e Ser Gln Leu Arg Phe               155              - #   160              - #   165                          - - TGC CTC ACG GGG CTT CTG GTG ATC CTG TAT GG - #G ATG TTG CTG CTT GTG          579                                                                       Cys Leu Thr Gly Leu Leu Val Ile Leu Tyr Gl - #y Met Leu Leu Leu Val           170                 1 - #75                 1 - #80                 1 -      #85                                                                              - - GAG GTC AAC GTC ATC AGA GTG AGG AGG TAC AT - #C TTC TTC AAG ACG        CCA      627                                                                    Glu Val Asn Val Ile Arg Val Arg Arg Tyr Il - #e Phe Phe Lys Thr Pro                          190  - #               195  - #               200              - - CGG GAG GTG AAG CCC CCT GAG GAC CTG CAG GA - #C CTG GGT GTG CGC TTT          675                                                                       Arg Glu Val Lys Pro Pro Glu Asp Leu Gln As - #p Leu Gly Val Arg Phe                       205      - #           210      - #           215                  - - CTG CAG CCC TTC GTT AAC CTG CTG TCA AAG GG - #G ACC TAT TGG TGG ATG          723                                                                       Leu Gln Pro Phe Val Asn Leu Leu Ser Lys Gl - #y Thr Tyr Trp Trp Met                   220          - #       225          - #       230                      - - AAT GCC TTC ATC AAG ACG GCC CAC AAG AAG CC - #C ATC GAC CTG CGG GCC          771                                                                       Asn Ala Phe Ile Lys Thr Ala His Lys Lys Pr - #o Ile Asp Leu Arg Ala               235              - #   240              - #   245                          - - ATC GCG AAG CTG CCC ATC GCC ATG AGA GCC CT - #C ACC AAC TAT CAG CGC          819                                                                       Ile Ala Lys Leu Pro Ile Ala Met Arg Ala Le - #u Thr Asn Tyr Gln Arg           250                 2 - #55                 2 - #60                 2 -      #65                                                                              - - CTC TGC GTG GCC TTC GAT GCT CAG GCG CGG AA - #G GAC ACA CAG AGC        CCA      867                                                                    Leu Cys Val Ala Phe Asp Ala Gln Ala Arg Ly - #s Asp Thr Gln Ser Pro                          270  - #               275  - #               280              - - CAG GGT GCC CGG GCC ATC TGG AGG GCT CTA TG - #C CAT GCC TTT GGG AGA          915                                                                       Gln Gly Ala Arg Ala Ile Trp Arg Ala Leu Cy - #s His Ala Phe Gly Arg                       285      - #           290      - #           295                  - - CGC CTG ATC CTC AGC AGC ACA TTC CGC ATC CT - #G GCT GAC CTG TTG GGC          963                                                                       Arg Leu Ile Leu Ser Ser Thr Phe Arg Ile Le - #u Ala Asp Leu Leu Gly                   300          - #       305          - #       310                      - - TTC GCT GGA CCA CTC TGC ATC TTT GGG ATC GT - #G GAC CAC CTG GGG AAG         1011                                                                       Phe Ala Gly Pro Leu Cys Ile Phe Gly Ile Va - #l Asp His Leu Gly Lys               315              - #   320              - #   325                          - - GAG AAC CAC GTC TTC CAG CCC AAG ACA CAG TT - #T CTC GGG GTT TAC TTC         1059                                                                       Glu Asn His Val Phe Gln Pro Lys Thr Gln Ph - #e Leu Gly Val Tyr Phe           330                 3 - #35                 3 - #40                 3 -      #45                                                                              - - GTC TCT TCT CAA GAG TTC CTT GGC AAT GCC TA - #C GTC TTG GCC GTG        CTT     1107                                                                    Val Ser Ser Gln Glu Phe Leu Gly Asn Ala Ty - #r Val Leu Ala Val Leu                          350  - #               355  - #               360              - - CTG TTC CTT GCC CTG CTA CTG CAA AGG ACA TT - #C CTG CAA GCC TCA TAC         1155                                                                       Leu Phe Leu Ala Leu Leu Leu Gln Arg Thr Ph - #e Leu Gln Ala Ser Tyr                       365      - #           370      - #           375                  - - TAC GTC GCC ATT GAA ACT GGA ATT AAC CTG AG - #A GGA GCA ATC CAG ACC         1203                                                                       Tyr Val Ala Ile Glu Thr Gly Ile Asn Leu Ar - #g Gly Ala Ile Gln Thr                   380          - #       385          - #       390                      - - AAG ATT TAC AAT AAA ATC ATG CAC ATG TCC AC - #C TCC AAC CTG TCA ATG         1251                                                                       Lys Ile Tyr Asn Lys Ile Met His Met Ser Th - #r Ser Asn Leu Ser Met               395              - #   400              - #   405                          - - GGG GAA ATG ACT GCT GGG CAG ATC TGC AAC CT - #G GTG GCC ATC GAC ACA         1299                                                                       Gly Glu Met Thr Ala Gly Gln Ile Cys Asn Le - #u Val Ala Ile Asp Thr           410                 4 - #15                 4 - #20                 4 -      #25                                                                              - - AAC CAG CTC ATG TGG TTC TTC TTT CTG TGC CC - #A AAC CTC TGG ACG        ATG     1347                                                                    Asn Gln Leu Met Trp Phe Phe Phe Leu Cys Pr - #o Asn Leu Trp Thr Met                          430  - #               435  - #               440              - - CCA GTA CAG ATC ATT GTG GGC GTG ATC CTT CT - #C TAC TAC ATC CTT GGG         1395                                                                       Pro Val Gln Ile Ile Val Gly Val Ile Leu Le - #u Tyr Tyr Ile Leu Gly                       445      - #           450      - #           455                  - - GTC AGT GCC TTG ATT GGA GCA GCT GTC ATC AT - #T CTG CTG GCT CCT GTA         1443                                                                       Val Ser Ala Leu Ile Gly Ala Ala Val Ile Il - #e Leu Leu Ala Pro Val                   460          - #       465          - #       470                      - - CAG TAC TTT GTG GCC ACC AAG CTC TCC CAG GC - #A CAG CGG ACG ACC TTG         1491                                                                       Gln Tyr Phe Val Ala Thr Lys Leu Ser Gln Al - #a Gln Arg Thr Thr Leu               475              - #   480              - #   485                          - - GAG CAC TCC AAC GAG AGG CTG AAG CAG ACC AA - #C GAG ATG CTC CGG GGC         1539                                                                       Glu His Ser Asn Glu Arg Leu Lys Gln Thr As - #n Glu Met Leu Arg Gly           490                 4 - #95                 5 - #00                 5 -      #05                                                                              - - ATG AAG CTG CTC AAA CTG TAT GCG TGG GAG AG - #C ATC TTC TGC TCC        AGG     1587                                                                    Met Lys Leu Leu Lys Leu Tyr Ala Trp Glu Se - #r Ile Phe Cys Ser Arg                          510  - #               515  - #               520              - - GTG GAG GTG ACT CGC AGG AAG GAG ATG ACC AG - #C CTG AGG GCG TTT GCT         1635                                                                       Val Glu Val Thr Arg Arg Lys Glu Met Thr Se - #r Leu Arg Ala Phe Ala                       525      - #           530      - #           535                  - - GTC TAC ACT TCC ATC TCC ATC TTC ATG AAC AC - #A GCC ATC CCC ATT GCT         1683                                                                       Val Tyr Thr Ser Ile Ser Ile Phe Met Asn Th - #r Ala Ile Pro Ile Ala                   540          - #       545          - #       550                      - - GCC GTC CTC ATC ACC TTC GTG GGC CAC GTC AG - #C TTC TTC AAA GAG TCG         1731                                                                       Ala Val Leu Ile Thr Phe Val Gly His Val Se - #r Phe Phe Lys Glu Ser               555              - #   560              - #   565                          - - GAC TTG TCA CCC TCG GTG GCC TTT GCC TCC CT - #C TCT CTC TTC CAC ATC         1779                                                                       Asp Leu Ser Pro Ser Val Ala Phe Ala Ser Le - #u Ser Leu Phe His Ile           570                 5 - #75                 5 - #80                 5 -      #85                                                                              - - CTG GTC ACT CCA CTG TTC CTG CTG TCT AGC GT - #G GTT CGG TCC ACT        GTC     1827                                                                    Leu Val Thr Pro Leu Phe Leu Leu Ser Ser Va - #l Val Arg Ser Thr Val                          590  - #               595  - #               600              - - AAA GCC CTG GTG AGC GTG CAA AAA CTG AGC GA - #G TTC CTG TCT AGT GCA         1875                                                                       Lys Ala Leu Val Ser Val Gln Lys Leu Ser Gl - #u Phe Leu Ser Ser Ala                       605      - #           610      - #           615                  - - GAG ATC CGT GAG GAG CAG TGT GCC CCC CGA GA - #G CCT GCA CCC CAA GGC         1923                                                                       Glu Ile Arg Glu Glu Gln Cys Ala Pro Arg Gl - #u Pro Ala Pro Gln Gly                   620          - #       625          - #       630                      - - CAA GCC GGC AAG TAC CAG GCA GTG CCC CTC AA - #G GTT GTG AAC CGC AAA         1971                                                                       Gln Ala Gly Lys Tyr Gln Ala Val Pro Leu Ly - #s Val Val Asn Arg Lys               635              - #   640              - #   645                          - - CGC CCA GCC CGG GAA GAG GTC CGG GAC CTC CT - #G GGC CCA CTG CAG AGG         2019                                                                       Arg Pro Ala Arg Glu Glu Val Arg Asp Leu Le - #u Gly Pro Leu Gln Arg           650                 6 - #55                 6 - #60                 6 -      #65                                                                              - - CTG GCC CCT AGC ATG GAC GGG GAT GCT GAC AA - #C TTC TGT GTC CAG        ATC     2067                                                                    Leu Ala Pro Ser Met Asp Gly Asp Ala Asp As - #n Phe Cys Val Gln Ile                          670  - #               675  - #               680              - - ATC GGA GGC TTC TTC ACC TGG ACC CCT GAT GG - #A ATC CCC ACT CTG TCC         2115                                                                       Ile Gly Gly Phe Phe Thr Trp Thr Pro Asp Gl - #y Ile Pro Thr Leu Ser                       685      - #           690      - #           695                  - - AAC ATC ACC ATC CGT ATT CCC CGA GGT CAG CT - #A ACC ATG ATT GTG GGG         2163                                                                       Asn Ile Thr Ile Arg Ile Pro Arg Gly Gln Le - #u Thr Met Ile Val Gly                   700          - #       705          - #       710                      - - CAG GTG GGC TGC GGC AAG TCC TCG CTC CTC CT - #C GCC ACC CTG GGG GAG         2211                                                                       Gln Val Gly Cys Gly Lys Ser Ser Leu Leu Le - #u Ala Thr Leu Gly Glu               715              - #   720              - #   725                          - - ATG CAG AAG GTG TCG GGG GCC GTC TTC TGG AA - #C AGC AAC CTT CCG GAC         2259                                                                       Met Gln Lys Val Ser Gly Ala Val Phe Trp As - #n Ser Asn Leu Pro Asp           730                 7 - #35                 7 - #40                 7 -      #45                                                                              - - AGC GAG GGG AGA GGA CCC CAG CAG CCC AGA GC - #G GGA GAC AGC AGC        TGG     2307                                                                    Ser Glu Gly Arg Gly Pro Gln Gln Pro Arg Al - #a Gly Asp Ser Ser Trp                          750  - #               755  - #               760              - - CTC GGA TAT CAG GAG CAG AGG CCC CGT GGC TA - #C GCA TCT CAG AAA CCA         2355                                                                       Leu Gly Tyr Gln Glu Gln Arg Pro Arg Gly Ty - #r Ala Ser Gln Lys Pro                       765      - #           770      - #           775                  - - TGG CTG CTA AAC GCC ACC GTG GAA GAG AAC AT - #C ACC TTC GAG AGT CCC         2403                                                                       Trp Leu Leu Asn Ala Thr Val Glu Glu Asn Il - #e Thr Phe Glu Ser Pro                   780          - #       785          - #       790                      - - TTC AAT CCG CAG CGG TAC AAG ATG GTC ATC GA - #A GCC TGC TCC CTG CAG         2451                                                                       Phe Asn Pro Gln Arg Tyr Lys Met Val Ile Gl - #u Ala Cys Ser Leu Gln               795              - #   800              - #   805                          - - CCG GAC ATA GAC ATC CTG CCC CAC GGA GAC CA - #G ACT CAG ATT GGG GAA         2499                                                                       Pro Asp Ile Asp Ile Leu Pro His Gly Asp Gl - #n Thr Gln Ile Gly Glu           810                 8 - #15                 8 - #20                 8 -      #25                                                                              - - CGG GGC ATC AAC CTG TCT GGT GGT CAG CGT CC - #A GAT CAG TGT GGT        CCA     2547                                                                    Arg Gly Ile Asn Leu Ser Gly Gly Gln Arg Pr - #o Asp Gln Cys Gly Pro                          830  - #               835  - #               840              - - GAG CCC TCT ACC AGC AGA CCA ATG TTC GTC TT - #C TTG GAT GAC CCC TTC         2595                                                                       Glu Pro Ser Thr Ser Arg Pro Met Phe Val Ph - #e Leu Asp Asp Pro Phe                       845      - #           850      - #           855                  - - TCA GCT TTG GAT GTC CAT CTG AGT GAC CAC CT - #G ATG CAG GCC GGC ATC         2643                                                                       Ser Ala Leu Asp Val His Leu Ser Asp His Le - #u Met Gln Ala Gly Ile                   860          - #       865          - #       870                      - - CTT GAG CTG CTC CGG GAT GAC AAG AGG ACA GT - #G GTC TTG GTG ACC CAC         2691                                                                       Leu Glu Leu Leu Arg Asp Asp Lys Arg Thr Va - #l Val Leu Val Thr His               875              - #   880              - #   885                          - - AAG CTA CAG TAT CTG CCT CAT GCA GAC TGG AT - #C ATT GCC ATG AAG GAT         2739                                                                       Lys Leu Gln Tyr Leu Pro His Ala Asp Trp Il - #e Ile Ala Met Lys Asp           890                 8 - #95                 9 - #00                 9 -      #05                                                                              - - GGG ACC ATT CAG AGG GAA GGG ACG CTC AAG GA - #C TTC CAG AGG TCC        GAG     2787                                                                    Gly Thr Ile Gln Arg Glu Gly Thr Leu Lys As - #p Phe Gln Arg Ser Glu                          910  - #               915  - #               920              - - TGC CAG CTC TTT GAG CAC TGG AAG ACC CTC AT - #G AAC CGG CAG GAC CAA         2835                                                                       Cys Gln Leu Phe Glu His Trp Lys Thr Leu Me - #t Asn Arg Gln Asp Gln                       925      - #           930      - #           935                  - - GAG CTG GAG AAG GAG ACA GTC ATG GAG AGG AA - #A GCC TCA GAG CCA TCT         2883                                                                       Glu Leu Glu Lys Glu Thr Val Met Glu Arg Ly - #s Ala Ser Glu Pro Ser                   940          - #       945          - #       950                      - - CAG GGC CTG CCC CGT GCC ATG TCC TCC AGA GA - #C GGC CTT CTG CTG GAT         2931                                                                       Gln Gly Leu Pro Arg Ala Met Ser Ser Arg As - #p Gly Leu Leu Leu Asp               955              - #   960              - #   965                          - - GAG GAA GAG GAG GAA GAG GAG GCA GCC GAA AG - #C GAG GAA GAT GAC AAC         2979                                                                       Glu Glu Glu Glu Glu Glu Glu Ala Ala Glu Se - #r Glu Glu Asp Asp Asn           970                 9 - #75                 9 - #80                 9 -      #85                                                                              - - TTA TCT TCA GTG CTG CAT CAG CGA GCT AAG AT - #C CCC TGG CGA GCC        TGC     3027                                                                    Leu Ser Ser Val Leu His Gln Arg Ala Lys Il - #e Pro Trp Arg Ala Cys                          990  - #               995  - #               1000             - - ACT AAG TAT CTG TCC TCT GCT GGC ATT CTG CT - #C CTG TCC CTG CTT GTC         3075                                                                       Thr Lys Tyr Leu Ser Ser Ala Gly Ile Leu Le - #u Leu Ser Leu Leu Val                       1005     - #           1010      - #          1015                 - - TTC TCC CAG CTG CTC AAG CAC ATG GTC TTG GT - #G GCC ATT GAT TAT TGG         3123                                                                       Phe Ser Gln Leu Leu Lys His Met Val Leu Va - #l Ala Ile Asp Tyr Trp                   1020         - #       1025          - #      1030                     - - CTG GCC AAG TGG ACG GAC AGT GCC CTG GTC CT - #G AGC CCC GCT GCC AGG         3171                                                                       Leu Ala Lys Trp Thr Asp Ser Ala Leu Val Le - #u Ser Pro Ala Ala Arg               1035             - #   1040              - #  1045                         - - AAC TGT TCG CTC AGC CAG GAA TGT GAC CTG GA - #C CAG TCT GTC TAT GCC         3219                                                                       Asn Cys Ser Leu Ser Gln Glu Cys Asp Leu As - #p Gln Ser Val Tyr Ala           1050                1055 - #                1060 - #               1065        - - ATG GTA TTC ACC TTG CTC TGC AGC CTG GGT AT - #C GTG CTG TGC CTG GTC         3267                                                                       Met Val Phe Thr Leu Leu Cys Ser Leu Gly Il - #e Val Leu Cys Leu Val                           1070 - #               1075  - #              1080             - - ACC TCT GTC ACT GTG GAG TGG ACG GGA CTG AA - #G GTG GCC AAG AGG CTA         3315                                                                       Thr Ser Val Thr Val Glu Trp Thr Gly Leu Ly - #s Val Ala Lys Arg Leu                       1085     - #           1090      - #          1095                 - - CAC CGC AGC CTG CTC AAC CGC ATC ATC CTG GC - #C CCC ATG AGG TTC TTT         3363                                                                       His Arg Ser Leu Leu Asn Arg Ile Ile Leu Al - #a Pro Met Arg Phe Phe                   1100         - #       1105          - #      1110                     - - GAG ACC ACA CCC CTC GGG AGT ATC CTG AAC AG - #A TTT TCA TCC GAC TGT         3411                                                                       Glu Thr Thr Pro Leu Gly Ser Ile Leu Asn Ar - #g Phe Ser Ser Asp Cys               1115             - #   1120              - #  1125                         - - AAC ACC ATT GAC CAG CAC ATC CCA TCC ACG CT - #G GAG TGT CTG AGC CGG         3459                                                                       Asn Thr Ile Asp Gln His Ile Pro Ser Thr Le - #u Glu Cys Leu Ser Arg           1130                1135 - #                1140 - #               1145        - - TCC ACC CTG CTG TGT GTC TCC GCC CTG ACT GT - #C ATC TCC TAT GTC ACA         3507                                                                       Ser Thr Leu Leu Cys Val Ser Ala Leu Thr Va - #l Ile Ser Tyr Val Thr                           1150 - #               1155  - #              1160             - - CCC GTG TTC CTC GTG GCC CTC TTA CCC CTA GC - #T GTT GTG TGC TAC TTC         3555                                                                       Pro Val Phe Leu Val Ala Leu Leu Pro Leu Al - #a Val Val Cys Tyr Phe                       1165     - #           1170      - #          1175                 - - ATT CAG AAG TAC TTC CGA GTG GCA TCC AGG GA - #C CTG CAG CAG CTG GAC         3603                                                                       Ile Gln Lys Tyr Phe Arg Val Ala Ser Arg As - #p Leu Gln Gln Leu Asp                   1180         - #       1185          - #      1190                     - - GAC ACG ACG CAG CTC CCG CTC GTC TCA CAC TT - #T GCT GAA ACT GTG GAG         3651                                                                       Asp Thr Thr Gln Leu Pro Leu Val Ser His Ph - #e Ala Glu Thr Val Glu               1195             - #   1200              - #  1205                         - - GGA CTC ACC ACC ATC CGT GCC TTC AGG TAC GA - #G GCC CGG TTC CAG CAG         3699                                                                       Gly Leu Thr Thr Ile Arg Ala Phe Arg Tyr Gl - #u Ala Arg Phe Gln Gln           1210                1215 - #                1220 - #               1225        - - AAG CTT CTA GAA TAT ACC GAC TCC AAC AAC AT - #C GCC TCC CTC TTC CTC         3747                                                                       Lys Leu Leu Glu Tyr Thr Asp Ser Asn Asn Il - #e Ala Ser Leu Phe Leu                           1230 - #               1235  - #              1240             - - ACG GCA GCC AAC AGA TGG CTG GAA GTC TGC AT - #G GAG TAC ATC GGA GCG         3795                                                                       Thr Ala Ala Asn Arg Trp Leu Glu Val Cys Me - #t Glu Tyr Ile Gly Ala                       1245     - #           1250      - #          1255                 - - TGC GTG GTA CTC ATT GCG GCT GCC ACC TCC AT - #C TCC AAC TCC CTG CAC         3843                                                                       Cys Val Val Leu Ile Ala Ala Ala Thr Ser Il - #e Ser Asn Ser Leu His                   1260         - #       1265          - #      1270                     - - AGG GAA CTT TCT GCT GGC CTG GTG GGC CTG GG - #C CTC ACC TAT GCC TTG         3891                                                                       Arg Glu Leu Ser Ala Gly Leu Val Gly Leu Gl - #y Leu Thr Tyr Ala Leu               1275             - #   1280              - #  1285                         - - ATG GTC TCC AAC TAC CTC AAC TGG ATG GTG AG - #G AAC CTG GCG GAC ATG         3939                                                                       Met Val Ser Asn Tyr Leu Asn Trp Met Val Ar - #g Asn Leu Ala Asp Met           1290                1295 - #                1300 - #               1305        - - GAG ATC CAG CTG GGG GCT GTG AAG AGG ATC CA - #C GCA CTC CTG AAA ACC         3987                                                                       Glu Ile Gln Leu Gly Ala Val Lys Arg Ile Hi - #s Ala Leu Leu Lys Thr                           1310 - #               1315  - #              1320             - - GAG GCG GAG AGC TAT GAG GGG CTC CTG GCG CC - #G TCG TTG ATC CCC AAG         4035                                                                       Glu Ala Glu Ser Tyr Glu Gly Leu Leu Ala Pr - #o Ser Leu Ile Pro Lys                       1325     - #           1330      - #          1335                 - - AAC TGG CCA GAC CAA GGG AAG ATC CAA ATT CA - #G AAC CTG AGC GTG CGC         4083                                                                       Asn Trp Pro Asp Gln Gly Lys Ile Gln Ile Gl - #n Asn Leu Ser Val Arg                   1340         - #       1345          - #      1350                     - - TAT GAC AGC TCC CTG AAG CCA GTG CTG AAG CA - #T GTC AAC ACC CTC ATC         4131                                                                       Tyr Asp Ser Ser Leu Lys Pro Val Leu Lys Hi - #s Val Asn Thr Leu Ile               1355             - #   1360              - #  1365                         - - TCC CCG GGG CAG AAG ATC GGG ATC TGC GGC CG - #C ACA GGC AGC GGG AAG         4179                                                                       Ser Pro Gly Gln Lys Ile Gly Ile Cys Gly Ar - #g Thr Gly Ser Gly Lys           1370                1375 - #                1380 - #               1385        - - TCC TCC TTC TCC CTG GCC TTT TTC CGA ATG GT - #G GAC ATG TTT GAA GGA         4227                                                                       Ser Ser Phe Ser Leu Ala Phe Phe Arg Met Va - #l Asp Met Phe Glu Gly                           1390 - #               1395  - #              1400             - - CGC ATC ATC ATT GAT GGC ATC GAC ATC GCC AA - #G CTG CCA CTT CAC ACG         4275                                                                       Arg Ile Ile Ile Asp Gly Ile Asp Ile Ala Ly - #s Leu Pro Leu His Thr                       1405     - #           1410      - #          1415                 - - CTG CGC TCA CGC CTG TCC ATC ATC CTA CAG GA - #C CCC GTC CTC TTC AGC         4323                                                                       Leu Arg Ser Arg Leu Ser Ile Ile Leu Gln As - #p Pro Val Leu Phe Ser                   1420         - #       1425          - #      1430                     - - GGC ACG ATC AGA TTC AAC CTG GAC CCC GAG AA - #G AAA TGC TCA GAC AGC         4371                                                                       Gly Thr Ile Arg Phe Asn Leu Asp Pro Glu Ly - #s Lys Cys Ser Asp Ser               1435             - #   1440              - #  1445                         - - ACA CTG TGG GAG GCC CTG GAG ATC GCC CAG CT - #G AAG CTG GTA GTG AAG         4419                                                                       Thr Leu Trp Glu Ala Leu Glu Ile Ala Gln Le - #u Lys Leu Val Val Lys           1450                1455 - #                1460 - #               1465        - - GCA CTG CCA GGA GGC CTA GAT GCC ATC ATC AC - #A GAA GGA GGG GAG AAT         4467                                                                       Ala Leu Pro Gly Gly Leu Asp Ala Ile Ile Th - #r Glu Gly Gly Glu Asn                           1470 - #               1475  - #              1480             - - TTT AGC CAG GGC CAG AGG CAG CTG TTC TGC CT - #G GCC CGG GCC TTC GTG         4515                                                                       Phe Ser Gln Gly Gln Arg Gln Leu Phe Cys Le - #u Ala Arg Ala Phe Val                       1485     - #           1490      - #          1495                 - - AGG AAG ACC AGC ATC TTC ATC ATG GAT GAA GC - #A ACC GCC TCC ATC GAC         4563                                                                       Arg Lys Thr Ser Ile Phe Ile Met Asp Glu Al - #a Thr Ala Ser Ile Asp                   1500         - #       1505          - #      1510                     - - ATG GCT ACG GAG AAC ATC CTC CAG AAG GTG GT - #G ATG ACA GCC TTC GCA         4611                                                                       Met Ala Thr Glu Asn Ile Leu Gln Lys Val Va - #l Met Thr Ala Phe Ala               1515             - #   1520              - #  1525                         - - GAC CGC ACG GTG GTC ACC ATC GCG CAT CGT GT - #G CAC ACC ATC CTG AGT         4659                                                                       Asp Arg Thr Val Val Thr Ile Ala His Arg Va - #l His Thr Ile Leu Ser           1530                1535 - #                1540 - #               1545        - - GCA GAC CTG GTG ATG GTC CTC AAG AGG GGT GC - #T ATC CTG GAG TTT GAC         4707                                                                       Ala Asp Leu Val Met Val Leu Lys Arg Gly Al - #a Ile Leu Glu Phe Asp                           1550 - #               1555  - #              1560             - - AAG CCA GAG ACG CTC CTC AGC CAG AAG GAC AG - #C GTG TTC GCC TCC TTT         4755                                                                       Lys Pro Glu Thr Leu Leu Ser Gln Lys Asp Se - #r Val Phe Ala Ser Phe                       1565     - #           1570      - #          1575                 - - GTC CGT GCG GAC AAG TGACTTACCG GAGCCAAAGT GCCACCCCG - #C GCCTCGCTTG         4810                                                                       Val Arg Ala Asp Lys                                                                   1580                                                                   - - CTTGCCTAGG ATTTCTAACT GCAAATCACT TGTAAATAAA TTAATTCTTT GC -             #TAAAAAAA   4870                                                                 - - AAAAAAA                 - #                  - #                       - #        4877                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:9:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1582 amino - #acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                               - - Met Pro Leu Ala Phe Cys Gly Thr Glu Asn Hi - #s Ser Ala Ala Tyr        Arg                                                                               1               5 - #                 10 - #                 15             - - Val Asp Gln Gly Val Leu Asn Asn Gly Cys Ph - #e Val Asp Ala Leu Asn                   20     - #             25     - #             30                  - - Val Val Pro His Val Phe Leu Leu Phe Ile Th - #r Phe Pro Ile Leu Phe               35         - #         40         - #         45                      - - Ile Gly Trp Gly Ser Gln Ser Ser Lys Val Hi - #s Ile His His Ser Thr           50             - #     55             - #     60                          - - Trp Leu His Phe Pro Gly His Asn Leu Arg Tr - #p Ile Leu Thr Phe Ile       65                 - # 70                 - # 75                 - # 80       - - Leu Leu Phe Val Leu Val Cys Glu Ile Ala Gl - #u Gly Ile Leu Ser Asp                       85 - #                 90 - #                 95              - - Gly Val Thr Glu Ser Arg His Leu His Leu Ty - #r Met Pro Ala Gly Met                  100      - #           105      - #           110                  - - Ala Phe Met Ala Ala Ile Thr Ser Val Val Ty - #r Tyr His Asn Ile Glu              115          - #       120          - #       125                      - - Thr Ser Asn Phe Pro Lys Leu Leu Ile Ala Le - #u Leu Ile Tyr Trp Thr          130              - #   135              - #   140                          - - Leu Ala Phe Ile Thr Lys Thr Ile Lys Phe Va - #l Lys Phe Tyr Asp His      145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - Ala Ile Gly Phe Ser Gln Leu Arg Phe Cys Le - #u Thr Gly Leu Leu        Val                                                                                             165  - #               170  - #               175             - - Ile Leu Tyr Gly Met Leu Leu Leu Val Glu Va - #l Asn Val Ile Arg Val                  180      - #           185      - #           190                  - - Arg Arg Tyr Ile Phe Phe Lys Thr Pro Arg Gl - #u Val Lys Pro Pro Glu              195          - #       200          - #       205                      - - Asp Leu Gln Asp Leu Gly Val Arg Phe Leu Gl - #n Pro Phe Val Asn Leu          210              - #   215              - #   220                          - - Leu Ser Lys Gly Thr Tyr Trp Trp Met Asn Al - #a Phe Ile Lys Thr Ala      225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - His Lys Lys Pro Ile Asp Leu Arg Ala Ile Al - #a Lys Leu Pro Ile        Ala                                                                                             245  - #               250  - #               255             - - Met Arg Ala Leu Thr Asn Tyr Gln Arg Leu Cy - #s Val Ala Phe Asp Ala                  260      - #           265      - #           270                  - - Gln Ala Arg Lys Asp Thr Gln Ser Pro Gln Gl - #y Ala Arg Ala Ile Trp              275          - #       280          - #       285                      - - Arg Ala Leu Cys His Ala Phe Gly Arg Arg Le - #u Ile Leu Ser Ser Thr          290              - #   295              - #   300                          - - Phe Arg Ile Leu Ala Asp Leu Leu Gly Phe Al - #a Gly Pro Leu Cys Ile      305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - Phe Gly Ile Val Asp His Leu Gly Lys Glu As - #n His Val Phe Gln        Pro                                                                                             325  - #               330  - #               335             - - Lys Thr Gln Phe Leu Gly Val Tyr Phe Val Se - #r Ser Gln Glu Phe Leu                  340      - #           345      - #           350                  - - Gly Asn Ala Tyr Val Leu Ala Val Leu Leu Ph - #e Leu Ala Leu Leu Leu              355          - #       360          - #       365                      - - Gln Arg Thr Phe Leu Gln Ala Ser Tyr Tyr Va - #l Ala Ile Glu Thr Gly          370              - #   375              - #   380                          - - Ile Asn Leu Arg Gly Ala Ile Gln Thr Lys Il - #e Tyr Asn Lys Ile Met      385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - His Met Ser Thr Ser Asn Leu Ser Met Gly Gl - #u Met Thr Ala Gly        Gln                                                                                             405  - #               410  - #               415             - - Ile Cys Asn Leu Val Ala Ile Asp Thr Asn Gl - #n Leu Met Trp Phe Phe                  420      - #           425      - #           430                  - - Phe Leu Cys Pro Asn Leu Trp Thr Met Pro Va - #l Gln Ile Ile Val Gly              435          - #       440          - #       445                      - - Val Ile Leu Leu Tyr Tyr Ile Leu Gly Val Se - #r Ala Leu Ile Gly Ala          450              - #   455              - #   460                          - - Ala Val Ile Ile Leu Leu Ala Pro Val Gln Ty - #r Phe Val Ala Thr Lys      465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - Leu Ser Gln Ala Gln Arg Thr Thr Leu Glu Hi - #s Ser Asn Glu Arg        Leu                                                                                             485  - #               490  - #               495             - - Lys Gln Thr Asn Glu Met Leu Arg Gly Met Ly - #s Leu Leu Lys Leu Tyr                  500      - #           505      - #           510                  - - Ala Trp Glu Ser Ile Phe Cys Ser Arg Val Gl - #u Val Thr Arg Arg Lys              515          - #       520          - #       525                      - - Glu Met Thr Ser Leu Arg Ala Phe Ala Val Ty - #r Thr Ser Ile Ser Ile          530              - #   535              - #   540                          - - Phe Met Asn Thr Ala Ile Pro Ile Ala Ala Va - #l Leu Ile Thr Phe Val      545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - Gly His Val Ser Phe Phe Lys Glu Ser Asp Le - #u Ser Pro Ser Val        Ala                                                                                             565  - #               570  - #               575             - - Phe Ala Ser Leu Ser Leu Phe His Ile Leu Va - #l Thr Pro Leu Phe Leu                  580      - #           585      - #           590                  - - Leu Ser Ser Val Val Arg Ser Thr Val Lys Al - #a Leu Val Ser Val Gln              595          - #       600          - #       605                      - - Lys Leu Ser Glu Phe Leu Ser Ser Ala Glu Il - #e Arg Glu Glu Gln Cys          610              - #   615              - #   620                          - - Ala Pro Arg Glu Pro Ala Pro Gln Gly Gln Al - #a Gly Lys Tyr Gln Ala      625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - Val Pro Leu Lys Val Val Asn Arg Lys Arg Pr - #o Ala Arg Glu Glu        Val                                                                                             645  - #               650  - #               655             - - Arg Asp Leu Leu Gly Pro Leu Gln Arg Leu Al - #a Pro Ser Met Asp Gly                  660      - #           665      - #           670                  - - Asp Ala Asp Asn Phe Cys Val Gln Ile Ile Gl - #y Gly Phe Phe Thr Trp              675          - #       680          - #       685                      - - Thr Pro Asp Gly Ile Pro Thr Leu Ser Asn Il - #e Thr Ile Arg Ile Pro          690              - #   695              - #   700                          - - Arg Gly Gln Leu Thr Met Ile Val Gly Gln Va - #l Gly Cys Gly Lys Ser      705                 7 - #10                 7 - #15                 7 -      #20                                                                              - - Ser Leu Leu Leu Ala Thr Leu Gly Glu Met Gl - #n Lys Val Ser Gly        Ala                                                                                             725  - #               730  - #               735             - - Val Phe Trp Asn Ser Asn Leu Pro Asp Ser Gl - #u Gly Arg Gly Pro Gln                  740      - #           745      - #           750                  - - Gln Pro Arg Ala Gly Asp Ser Ser Trp Leu Gl - #y Tyr Gln Glu Gln Arg              755          - #       760          - #       765                      - - Pro Arg Gly Tyr Ala Ser Gln Lys Pro Trp Le - #u Leu Asn Ala Thr Val          770              - #   775              - #   780                          - - Glu Glu Asn Ile Thr Phe Glu Ser Pro Phe As - #n Pro Gln Arg Tyr Lys      785                 7 - #90                 7 - #95                 8 -      #00                                                                              - - Met Val Ile Glu Ala Cys Ser Leu Gln Pro As - #p Ile Asp Ile Leu        Pro                                                                                             805  - #               810  - #               815             - - His Gly Asp Gln Thr Gln Ile Gly Glu Arg Gl - #y Ile Asn Leu Ser Gly                  820      - #           825      - #           830                  - - Gly Gln Arg Pro Asp Gln Cys Gly Pro Glu Pr - #o Ser Thr Ser Arg Pro              835          - #       840          - #       845                      - - Met Phe Val Phe Leu Asp Asp Pro Phe Ser Al - #a Leu Asp Val His Leu          850              - #   855              - #   860                          - - Ser Asp His Leu Met Gln Ala Gly Ile Leu Gl - #u Leu Leu Arg Asp Asp      865                 8 - #70                 8 - #75                 8 -      #80                                                                              - - Lys Arg Thr Val Val Leu Val Thr His Lys Le - #u Gln Tyr Leu Pro        His                                                                                             885  - #               890  - #               895             - - Ala Asp Trp Ile Ile Ala Met Lys Asp Gly Th - #r Ile Gln Arg Glu Gly                  900      - #           905      - #           910                  - - Thr Leu Lys Asp Phe Gln Arg Ser Glu Cys Gl - #n Leu Phe Glu His Trp              915          - #       920          - #       925                      - - Lys Thr Leu Met Asn Arg Gln Asp Gln Glu Le - #u Glu Lys Glu Thr Val          930              - #   935              - #   940                          - - Met Glu Arg Lys Ala Ser Glu Pro Ser Gln Gl - #y Leu Pro Arg Ala Met      945                 9 - #50                 9 - #55                 9 -      #60                                                                              - - Ser Ser Arg Asp Gly Leu Leu Leu Asp Glu Gl - #u Glu Glu Glu Glu        Glu                                                                                             965  - #               970  - #               975             - - Ala Ala Glu Ser Glu Glu Asp Asp Asn Leu Se - #r Ser Val Leu His Gln                  980      - #           985      - #           990                  - - Arg Ala Lys Ile Pro Trp Arg Ala Cys Thr Ly - #s Tyr Leu Ser Ser Ala              995          - #       1000          - #      1005                     - - Gly Ile Leu Leu Leu Ser Leu Leu Val Phe Se - #r Gln Leu Leu Lys His          1010             - #   1015              - #  1020                         - - Met Val Leu Val Ala Ile Asp Tyr Trp Leu Al - #a Lys Trp Thr Asp Ser      1025                1030 - #                1035 - #               1040        - - Ala Leu Val Leu Ser Pro Ala Ala Arg Asn Cy - #s Ser Leu Ser Gln Glu                      1045 - #               1050  - #              1055             - - Cys Asp Leu Asp Gln Ser Val Tyr Ala Met Va - #l Phe Thr Leu Leu Cys                  1060     - #           1065      - #          1070                 - - Ser Leu Gly Ile Val Leu Cys Leu Val Thr Se - #r Val Thr Val Glu Trp              1075         - #       1080          - #      1085                     - - Thr Gly Leu Lys Val Ala Lys Arg Leu His Ar - #g Ser Leu Leu Asn Arg          1090             - #   1095              - #  1100                         - - Ile Ile Leu Ala Pro Met Arg Phe Phe Glu Th - #r Thr Pro Leu Gly Ser      1105                1110 - #                1115 - #               1120        - - Ile Leu Asn Arg Phe Ser Ser Asp Cys Asn Th - #r Ile Asp Gln His Ile                      1125 - #               1130  - #              1135             - - Pro Ser Thr Leu Glu Cys Leu Ser Arg Ser Th - #r Leu Leu Cys Val Ser                  1140     - #           1145      - #          1150                 - - Ala Leu Thr Val Ile Ser Tyr Val Thr Pro Va - #l Phe Leu Val Ala Leu              1155         - #       1160          - #      1165                     - - Leu Pro Leu Ala Val Val Cys Tyr Phe Ile Gl - #n Lys Tyr Phe Arg Val          1170             - #   1175              - #  1180                         - - Ala Ser Arg Asp Leu Gln Gln Leu Asp Asp Th - #r Thr Gln Leu Pro Leu      1185                1190 - #                1195 - #               1200        - - Val Ser His Phe Ala Glu Thr Val Glu Gly Le - #u Thr Thr Ile Arg Ala                      1205 - #               1210  - #              1215             - - Phe Arg Tyr Glu Ala Arg Phe Gln Gln Lys Le - #u Leu Glu Tyr Thr Asp                  1220     - #           1225      - #          1230                 - - Ser Asn Asn Ile Ala Ser Leu Phe Leu Thr Al - #a Ala Asn Arg Trp Leu              1235         - #       1240          - #      1245                     - - Glu Val Cys Met Glu Tyr Ile Gly Ala Cys Va - #l Val Leu Ile Ala Ala          1250             - #   1255              - #  1260                         - - Ala Thr Ser Ile Ser Asn Ser Leu His Arg Gl - #u Leu Ser Ala Gly Leu      1265                1270 - #                1275 - #               1280        - - Val Gly Leu Gly Leu Thr Tyr Ala Leu Met Va - #l Ser Asn Tyr Leu Asn                      1285 - #               1290  - #              1295             - - Trp Met Val Arg Asn Leu Ala Asp Met Glu Il - #e Gln Leu Gly Ala Val                  1300     - #           1305      - #          1310                 - - Lys Arg Ile His Ala Leu Leu Lys Thr Glu Al - #a Glu Ser Tyr Glu Gly              1315         - #       1320          - #      1325                     - - Leu Leu Ala Pro Ser Leu Ile Pro Lys Asn Tr - #p Pro Asp Gln Gly Lys          1330             - #   1335              - #  1340                         - - Ile Gln Ile Gln Asn Leu Ser Val Arg Tyr As - #p Ser Ser Leu Lys Pro      1345                1350 - #                1355 - #               1360        - - Val Leu Lys His Val Asn Thr Leu Ile Ser Pr - #o Gly Gln Lys Ile Gly                      1365 - #               1370  - #              1375             - - Ile Cys Gly Arg Thr Gly Ser Gly Lys Ser Se - #r Phe Ser Leu Ala Phe                  1380     - #           1385      - #          1390                 - - Phe Arg Met Val Asp Met Phe Glu Gly Arg Il - #e Ile Ile Asp Gly Ile              1395         - #       1400          - #      1405                     - - Asp Ile Ala Lys Leu Pro Leu His Thr Leu Ar - #g Ser Arg Leu Ser Ile          1410             - #   1415              - #  1420                         - - Ile Leu Gln Asp Pro Val Leu Phe Ser Gly Th - #r Ile Arg Phe Asn Leu      1425                1430 - #                1435 - #               1440        - - Asp Pro Glu Lys Lys Cys Ser Asp Ser Thr Le - #u Trp Glu Ala Leu Glu                      1445 - #               1450  - #              1455             - - Ile Ala Gln Leu Lys Leu Val Val Lys Ala Le - #u Pro Gly Gly Leu Asp                  1460     - #           1465      - #          1470                 - - Ala Ile Ile Thr Glu Gly Gly Glu Asn Phe Se - #r Gln Gly Gln Arg Gln              1475         - #       1480          - #      1485                     - - Leu Phe Cys Leu Ala Arg Ala Phe Val Arg Ly - #s Thr Ser Ile Phe Ile          1490             - #   1495              - #  1500                         - - Met Asp Glu Ala Thr Ala Ser Ile Asp Met Al - #a Thr Glu Asn Ile Leu      1505                1510 - #                1515 - #               1520        - - Gln Lys Val Val Met Thr Ala Phe Ala Asp Ar - #g Thr Val Val Thr Ile                      1525 - #               1530  - #              1535             - - Ala His Arg Val His Thr Ile Leu Ser Ala As - #p Leu Val Met Val Leu                  1540     - #           1545      - #          1550                 - - Lys Arg Gly Ala Ile Leu Glu Phe Asp Lys Pr - #o Glu Thr Leu Leu Ser              1555         - #       1560          - #      1565                     - - Gln Lys Asp Ser Val Phe Ala Ser Phe Val Ar - #g Ala Asp Lys                  1570             - #   1575              - #  1580                         - -  - - (2) INFORMATION FOR SEQ ID NO:10:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: Amino acid                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                              - - Met Pro Leu Ala Phe Cys Gly Thr                                            1               5                                                            - -  - - (2) INFORMATION FOR SEQ ID NO:11:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: Amino acid                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                              - - Asn His Ser Ala Ala Tyr Arg Val Asp Gln Gl - #y                            1               5                                                            - -  - - (2) INFORMATION FOR SEQ ID NO:12:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acids                                     - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                              - - CACGCTCAGG TTCTGGAT             - #                  - #                      - #  18                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:13:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acids                                     - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: YES                                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                              - - TCAACTGGAT GGTGAGGA             - #                  - #                      - #  18                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:14:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                              - - TGACATCGCC AAACTGC             - #                  - #                      - #   17                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:15:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: YES                                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                              - - TCCTGGCAGT GCCTTCA             - #                  - #                      - #   17                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:16:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: YES                                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                              - - TCCTCTCAGG GTCCAGGTTA            - #                  - #                      - # 20                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:17:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                              - - ACAAGGAGCC TGGGGAT             - #                  - #                      - #   17                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:18:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: YES                                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                              - - TGCATGGGTC CCAGTGA             - #                  - #                      - #   17                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:19:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 25 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                              - - TTGACCATTC ACCACATTGG TGTGC          - #                  - #                   25                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:20:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: YES                                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                              - - TCCTGGCAGT GCCTTCA             - #                  - #                      - #   17                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:21:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                              - - Met Pro Leu Ala Phe Cys Gly Thr                                          1                5                                                             - -  - - (2) INFORMATION FOR SEQ ID NO:22:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                              - - Asn His Ser Ala Ala Tyr Arg Val Asp Gln Gl - #y                          1                5  - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:23:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  26 base - # pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS:  sing - #le                                                 (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: Nucleic Acid                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                              - - GAGAGAAGCT TNTGNGGNGA NAANCA          - #                  - #                  26                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:24:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  28 base - # pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: Nucleic Acid                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                              - - GAGAGAGAAT TCCNTGNTCN ACNCNNTA         - #                  - #                 28                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:25:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  47 base - # pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: Nucleic Acid                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                              - - TTTTGCGGGA CGGAGAATCA CTCGGCCGCC TACCGCGTCG ACCAAGG   - #                    47                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:26:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  9 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: Nucleic Acid                                      - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                              - - GCCNCCAUG                - #                  - #                       - #          9                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:27:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4635 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: N-terminal                                        - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 37..4533                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                              - - GCGCGGAGCC GGAGCCGAGC CCGTGCGCGC GCCACC ATG CCT TTG - #GCC TTC TGC           54                                                                                         - #                  - #    Met Pro Leu Ala Phe Cys                           - #                  - #      1            - #   5           - - GGC ACC GAG AAC CAC TCG GCC GCC TAC CGG GT - #G GAC CAA GGC GTC CTC          102                                                                       Gly Thr Glu Asn His Ser Ala Ala Tyr Arg Va - #l Asp Gln Gly Val Leu                        10     - #             15     - #             20                  - - AAC AAC GGC TGC TTC GTG GAC GCG CTC AAT GT - #G GTG CCA CAT GTC TTT          150                                                                       Asn Asn Gly Cys Phe Val Asp Ala Leu Asn Va - #l Val Pro His Val Phe                    25         - #         30         - #         35                      - - CTG CTC TTC ATC ACC TTC CCC ATC CTC TTC AT - #C GGA TGG GGC AGC CAG          198                                                                       Leu Leu Phe Ile Thr Phe Pro Ile Leu Phe Il - #e Gly Trp Gly Ser Gln                40             - #     45             - #     50                          - - AGC TCC AAG GTG CAC ATT CAC CAC AGC ACC TG - #G CTC CAT TTC CCG GGG          246                                                                       Ser Ser Lys Val His Ile His His Ser Thr Tr - #p Leu His Phe Pro Gly            55                 - # 60                 - # 65                 - # 70       - - CAC AAC CTG CGC TGG ATC CTG ACC TTC ATA CT - #G CTC TTC GTC CTC GTG          294                                                                       His Asn Leu Arg Trp Ile Leu Thr Phe Ile Le - #u Leu Phe Val Leu Val                            75 - #                 80 - #                 85              - - TGT GAG ATC GCT GAG GGT ATC CTG TCT GAC GG - #G GTG ACA GAA TCC CGC          342                                                                       Cys Glu Ile Ala Glu Gly Ile Leu Ser Asp Gl - #y Val Thr Glu Ser Arg                        90     - #             95     - #            100                  - - CAC CTC CAC TTA TAC ATG CCA GCT GGG ATG GC - #A TTC ATG GCT GCC ATC          390                                                                       His Leu His Leu Tyr Met Pro Ala Gly Met Al - #a Phe Met Ala Ala Ile                   105          - #       110          - #       115                      - - ACC TCT GTG GTC TAC TAC CAT AAC ATT GAG AC - #C TCT AAC TTT CCC AAG          438                                                                       Thr Ser Val Val Tyr Tyr His Asn Ile Glu Th - #r Ser Asn Phe Pro Lys               120              - #   125              - #   130                          - - CTG CTG ATT GCT CTG CTC ATC TAC TGG ACC CT - #G GCC TTC ATC ACG AAG          486                                                                       Leu Leu Ile Ala Leu Leu Ile Tyr Trp Thr Le - #u Ala Phe Ile Thr Lys           135                 1 - #40                 1 - #45                 1 -      #50                                                                              - - ACC ATC AAG TTC GTC AAG TTC TAC GAC CAC GC - #C ATT GGC TTC TCT        CAG      534                                                                    Thr Ile Lys Phe Val Lys Phe Tyr Asp His Al - #a Ile Gly Phe Ser Gln                          155  - #               160  - #               165              - - CTG CGC TTC TGC CTC ACG GGG CTT CTG GTG AT - #C CTC TAC GGG ATG CTG          582                                                                       Leu Arg Phe Cys Leu Thr Gly Leu Leu Val Il - #e Leu Tyr Gly Met Leu                       170      - #           175      - #           180                  - - CTG CTT GTG GAG GTC AAT GTC ATC CGG GTG AG - #G AGA TAC GTC TTC TTC          630                                                                       Leu Leu Val Glu Val Asn Val Ile Arg Val Ar - #g Arg Tyr Val Phe Phe                   185          - #       190          - #       195                      - - AAG ACA CCA AGG GAA GTA AAG CCC CCC GAG GA - #C CTA CAG GAC CTG GGT          678                                                                       Lys Thr Pro Arg Glu Val Lys Pro Pro Glu As - #p Leu Gln Asp Leu Gly               200              - #   205              - #   210                          - - GTG CGC TTT CTG CAG CCC TTC GTT AAC CTG CT - #A TCA AAG GGG ACC TAC          726                                                                       Val Arg Phe Leu Gln Pro Phe Val Asn Leu Le - #u Ser Lys Gly Thr Tyr           215                 2 - #20                 2 - #25                 2 -      #30                                                                              - - TGG TGG ATG AAT GCC TTC ATC AAG ACT GCT CA - #C AAG AAG CCC ATC        GAC      774                                                                    Trp Trp Met Asn Ala Phe Ile Lys Thr Ala Hi - #s Lys Lys Pro Ile Asp                          235  - #               240  - #               245              - - CTG CGG GCC ATC GGG AAG CTG CCC ATT GCC AT - #G AGA GCC CTC ACC AAC          822                                                                       Leu Arg Ala Ile Gly Lys Leu Pro Ile Ala Me - #t Arg Ala Leu Thr Asn                       250      - #           255      - #           260                  - - TAC CAG CGA CTC TGC TTG GCC TTC GAT GCC CA - #G GCG CGG AAG GAC ACA          870                                                                       Tyr Gln Arg Leu Cys Leu Ala Phe Asp Ala Gl - #n Ala Arg Lys Asp Thr                   265          - #       270          - #       275                      - - CAG AGC CAG CAG GGT GCC CGG GCC ATC TGG AG - #G GCT CTC TGT CAT GCC          918                                                                       Gln Ser Gln Gln Gly Ala Arg Ala Ile Trp Ar - #g Ala Leu Cys His Ala               280              - #   285              - #   290                          - - TTT GGG AGA CGG CTG GTC CTC AGC AGC ACA TT - #C CGT ATC CTG GCC GAC          966                                                                       Phe Gly Arg Arg Leu Val Leu Ser Ser Thr Ph - #e Arg Ile Leu Ala Asp           295                 3 - #00                 3 - #05                 3 -      #10                                                                              - - CTC CTG GGC TTT GCT GGG CCA CTC TGC ATC TT - #C GGG ATC GTG GAC        CAC     1014                                                                    Leu Leu Gly Phe Ala Gly Pro Leu Cys Ile Ph - #e Gly Ile Val Asp His                          315  - #               320  - #               325              - - CTC GGG AAG GAG AAC CAC GTC TTC CAG CCC AA - #G ACA CAG TTT CTT GGA         1062                                                                       Leu Gly Lys Glu Asn His Val Phe Gln Pro Ly - #s Thr Gln Phe Leu Gly                       330      - #           335      - #           340                  - - GTT TAC TTT GTC TCA TCC CAA GAG TTC CTC GG - #C AAT GCC TAT GTC TTG         1110                                                                       Val Tyr Phe Val Ser Ser Gln Glu Phe Leu Gl - #y Asn Ala Tyr Val Leu                   345          - #       350          - #       355                      - - GCT GTT CTT CTG TTC CTT GCC CTC CTG CTG CA - #A AGG ACC TTT CTA CAA         1158                                                                       Ala Val Leu Leu Phe Leu Ala Leu Leu Leu Gl - #n Arg Thr Phe Leu Gln               360              - #   365              - #   370                          - - GCC TCG TAC TAC GTT GCC ATT GAA ACT GGG AT - #C AAC CTG AGA GGA GCA         1206                                                                       Ala Ser Tyr Tyr Val Ala Ile Glu Thr Gly Il - #e Asn Leu Arg Gly Ala           375                 3 - #80                 3 - #85                 3 -      #90                                                                              - - ATC CAG ACC AAG ATT TAC AAT AAG ATC ATG CA - #C TTG TCT ACT TCC        AAC     1254                                                                    Ile Gln Thr Lys Ile Tyr Asn Lys Ile Met Hi - #s Leu Ser Thr Ser Asn                          395  - #               400  - #               405              - - CTG TCC ATG GGG GAA ATG ACT GCT GGG CAG AT - #C TGC AAC CTG GTG GCC         1302                                                                       Leu Ser Met Gly Glu Met Thr Ala Gly Gln Il - #e Cys Asn Leu Val Ala                       410      - #           415      - #           420                  - - ATC GAC ACC AAC CAG CTC ATG TGG TTT TTC TT - #C TTA TGC CCA AAC CTC         1350                                                                       Ile Asp Thr Asn Gln Leu Met Trp Phe Phe Ph - #e Leu Cys Pro Asn Leu                   425          - #       430          - #       435                      - - TGG GCT ATG CCG GTA CAG ATC ATT GTG GGC GT - #G ATC CTC CTC TAC TAC         1398                                                                       Trp Ala Met Pro Val Gln Ile Ile Val Gly Va - #l Ile Leu Leu Tyr Tyr               440              - #   445              - #   450                          - - ATC CTT GGG GTC AGC GCC TTG ATT GGA GCG GC - #T GTC ATC ATT CTG CTG         1446                                                                       Ile Leu Gly Val Ser Ala Leu Ile Gly Ala Al - #a Val Ile Ile Leu Leu           455                 4 - #60                 4 - #65                 4 -      #70                                                                              - - GCT CCT GTA CAG TAC TTT GTG GCC ACC AAG CT - #G TCC CAG GCA CAG        CGG     1494                                                                    Ala Pro Val Gln Tyr Phe Val Ala Thr Lys Le - #u Ser Gln Ala Gln Arg                          475  - #               480  - #               485              - - ACG ACC CTG GAA TAT TCC AAT GAG AGG CTG AA - #G CAG ACC AAT GAG ATG         1542                                                                       Thr Thr Leu Glu Tyr Ser Asn Glu Arg Leu Ly - #s Gln Thr Asn Glu Met                       490      - #           495      - #           500                  - - CTC CGG GGC ATC AAG TTG CTC AAG CTC TAT GC - #G TGG GAG AAC ATC TTC         1590                                                                       Leu Arg Gly Ile Lys Leu Leu Lys Leu Tyr Al - #a Trp Glu Asn Ile Phe                   505          - #       510          - #       515                      - - TGC TCC AGG GTG GAG AAG ACA CGC AGG AAG GA - #A ATG ACC AGC CTC AGG         1638                                                                       Cys Ser Arg Val Glu Lys Thr Arg Arg Lys Gl - #u Met Thr Ser Leu Arg               520              - #   525              - #   530                          - - GCC TTC GCT GTC TAC ACC TCC ATC TCC ATC TT - #C ATG AAC ACA GCT ATC         1686                                                                       Ala Phe Ala Val Tyr Thr Ser Ile Ser Ile Ph - #e Met Asn Thr Ala Ile           535                 5 - #40                 5 - #45                 5 -      #50                                                                              - - CCC ATC GCT GCT GTC CTC ATC ACC TTC GTG GG - #C CAC GTC AGC TTC        TTC     1734                                                                    Pro Ile Ala Ala Val Leu Ile Thr Phe Val Gl - #y His Val Ser Phe Phe                          555  - #               560  - #               565              - - AAA GAG TCG GAC TTC TCG CCC TCG GTG GCC TT - #T GCC TCT CTC TCT CTC         1782                                                                       Lys Glu Ser Asp Phe Ser Pro Ser Val Ala Ph - #e Ala Ser Leu Ser Leu                       570      - #           575      - #           580                  - - TTC CAC ATC CTG GTC ACA CCG CTG TTC CTG CT - #G TCT AGT GTG GTT CGG         1830                                                                       Phe His Ile Leu Val Thr Pro Leu Phe Leu Le - #u Ser Ser Val Val Arg                   585          - #       590          - #       595                      - - TCC ACT GTC AAG GCC CTG GTG AGC GTG CAA AA - #G CTG AGT GAG TTC CTG         1878                                                                       Ser Thr Val Lys Ala Leu Val Ser Val Gln Ly - #s Leu Ser Glu Phe Leu               600              - #   605              - #   610                          - - TCC AGT GCA GAG ATC CGT GAG GAA CAG TGT GC - #C CCC CGA GAG CCC GCA         1926                                                                       Ser Ser Ala Glu Ile Arg Glu Glu Gln Cys Al - #a Pro Arg Glu Pro Ala           615                 6 - #20                 6 - #25                 6 -      #30                                                                              - - CCC CAA GGC CAA GCG GGC AAG TAC CAG GCG GT - #G CCC CTC AAG GTC        GTA     1974                                                                    Pro Gln Gly Gln Ala Gly Lys Tyr Gln Ala Va - #l Pro Leu Lys Val Val                          635  - #               640  - #               645              - - AAC CGC AAG CGC CCA GCC CGA GAA GAA GTC CG - #G GAC CTC TTG GGC CCA         2022                                                                       Asn Arg Lys Arg Pro Ala Arg Glu Glu Val Ar - #g Asp Leu Leu Gly Pro                       650      - #           655      - #           660                  - - CTG CAG AGG CTG ACT CCC AGC ACG GAT GGA GA - #C GCT GAC AAC TTC TGT         2070                                                                       Leu Gln Arg Leu Thr Pro Ser Thr Asp Gly As - #p Ala Asp Asn Phe Cys                   665          - #       670          - #       675                      - - GTC CAG ATC ATC GGA GGC TTC TTC ACC TGG AC - #C CCT GAT GGA ATC CCC         2118                                                                       Val Gln Ile Ile Gly Gly Phe Phe Thr Trp Th - #r Pro Asp Gly Ile Pro               680              - #   685              - #   690                          - - ACC CTG TCC AAC ATC ACC ATC CGT ATC CCC CG - #A GGT CAG CTG ACC ATG         2166                                                                       Thr Leu Ser Asn Ile Thr Ile Arg Ile Pro Ar - #g Gly Gln Leu Thr Met           695                 7 - #00                 7 - #05                 7 -      #10                                                                              - - ATC GTG GGG CAG GTG GGC TGT GGC AAG TCC TC - #G CTC CTT CTG GCC        ACC     2214                                                                    Ile Val Gly Gln Val Gly Cys Gly Lys Ser Se - #r Leu Leu Leu Ala Thr                          715  - #               720  - #               725              - - CTG GGG GAG ATG CAG AAG GTC TCT GGA GCT GT - #C TTC TGG AAC AGC CTT         2262                                                                       Leu Gly Glu Met Gln Lys Val Ser Gly Ala Va - #l Phe Trp Asn Ser Leu                       730      - #           735      - #           740                  - - CCA GAC AGC GAG GGG AGA AGA CCC CAG CAA CC - #C AGA GCG GGA GAC AGC         2310                                                                       Pro Asp Ser Glu Gly Arg Arg Pro Gln Gln Pr - #o Arg Ala Gly Asp Ser                   745          - #       750          - #       755                      - - GGC CGA TTC GGA TGC CAG GAG CAG AGG CCC TG - #T GGC TAC GCA TCT CAG         2358                                                                       Gly Arg Phe Gly Cys Gln Glu Gln Arg Pro Cy - #s Gly Tyr Ala Ser Gln               760              - #   765              - #   770                          - - AAA CCA TGG CTG CTA AAT GCC ACT GTG GAG GA - #G AAC ATC ACC TTC GAG         2406                                                                       Lys Pro Trp Leu Leu Asn Ala Thr Val Glu Gl - #u Asn Ile Thr Phe Glu           775                 7 - #80                 7 - #85                 7 -      #90                                                                              - - AGT CCC TTC AAT AAG CAA CGG TAC AAG ATG GT - #C ATC GAA GCC TGC        TCC     2454                                                                    Ser Pro Phe Asn Lys Gln Arg Tyr Lys Met Va - #l Ile Glu Ala Cys Ser                          795  - #               800  - #               805              - - CTG CAG CCA GAC ATA GAC ATC CTG CCC CAT GG - #A GAC CAG ACT CAG ATT         2502                                                                       Leu Gln Pro Asp Ile Asp Ile Leu Pro His Gl - #y Asp Gln Thr Gln Ile                       810      - #           815      - #           820                  - - GGG GAA CGA GGC ATC AAC TTG AGT ACT GGT GG - #T CAG CGT CCA GAT CAG         2550                                                                       Gly Glu Arg Gly Ile Asn Leu Ser Thr Gly Gl - #y Gln Arg Pro Asp Gln                   825          - #       830          - #       835                      - - TGT AGA CCC GAG CCC TCT ACC AGC ACA CCA AT - #G ATT GTC TTT TTG GAT         2598                                                                       Cys Arg Pro Glu Pro Ser Thr Ser Thr Pro Me - #t Ile Val Phe Leu Asp               840              - #   845              - #   850                          - - GAC CCT TTC TCG GCT CTG GAT GTC CAT CTG AG - #T GAC CAC CTA ATG CAG         2646                                                                       Asp Pro Phe Ser Ala Leu Asp Val His Leu Se - #r Asp His Leu Met Gln           855                 8 - #60                 8 - #65                 8 -      #70                                                                              - - GCT GGC ATC CTC GAG CTG CTC CGG GAT GAC AA - #G AGG ACA GTG GTC        TTG     2694                                                                    Ala Gly Ile Leu Glu Leu Leu Arg Asp Asp Ly - #s Arg Thr Val Val Leu                          875  - #               880  - #               885              - - GTG ACC CAC AAG CTA CAG TAC CTG CCT CAT GC - #T GAC TGG ATC ATT GCT         2742                                                                       Val Thr His Lys Leu Gln Tyr Leu Pro His Al - #a Asp Trp Ile Ile Ala                       890      - #           895      - #           900                  - - ATG AAG GAT GGC ACC ATT CAG AGG GAG GGG AC - #A CTC AAG GAC TTC CAG         2790                                                                       Met Lys Asp Gly Thr Ile Gln Arg Glu Gly Th - #r Leu Lys Asp Phe Gln                   905          - #       910          - #       915                      - - AGG TCT GAG TGC CAG CTC TTT GAG CAT TGG AA - #G ACC CTC ATG AAC CGG         2838                                                                       Arg Ser Glu Cys Gln Leu Phe Glu His Trp Ly - #s Thr Leu Met Asn Arg               920              - #   925              - #   930                          - - CAG GAC CAA GAG CTG GAG AAG GAG ACA GTC AT - #G GAG AGA AAA GCC CCA         2886                                                                       Gln Asp Gln Glu Leu Glu Lys Glu Thr Val Me - #t Glu Arg Lys Ala Pro           935                 9 - #40                 9 - #45                 9 -      #50                                                                              - - GAG CCA TCT CAG GGC CTG CCC CGT GCC ATG TC - #C TCA AGA GAT GGC        CTT     2934                                                                    Glu Pro Ser Gln Gly Leu Pro Arg Ala Met Se - #r Ser Arg Asp Gly Leu                          955  - #               960  - #               965              - - CTG CTG GAT GAG GAT GAG GAG GAA GAG GAG GC - #A GCC GAG AGC GAG GAA         2982                                                                       Leu Leu Asp Glu Asp Glu Glu Glu Glu Glu Al - #a Ala Glu Ser Glu Glu                       970      - #           975      - #           980                  - - GAT GAC AAC TTA TCC TCT GTG CTG CAT CAG CG - #A GCC AAG ATC CCA TGG         3030                                                                       Asp Asp Asn Leu Ser Ser Val Leu His Gln Ar - #g Ala Lys Ile Pro Trp                   985          - #       990          - #       995                      - - CGA GCC TGC ACC AAG TAT TTG TCC TCT GCT GG - #C ATC CTG CTC CTG TCC         3078                                                                       Arg Ala Cys Thr Lys Tyr Leu Ser Ser Ala Gl - #y Ile Leu Leu Leu Ser               1000             - #   1005              - #  1010                         - - CTG CTT GTC TTC TCC CAG CTG CTC AAG CAC AT - #G GTC TTG GTG GCC ATT         3126                                                                       Leu Leu Val Phe Ser Gln Leu Leu Lys His Me - #t Val Leu Val Ala Ile           1015                1020 - #                1025 - #               1030        - - GAC TAC TGG CTG GCC AAG TGG ACG GAC AGT GC - #C CTG GTC CTG AGC CCC         3174                                                                       Asp Tyr Trp Leu Ala Lys Trp Thr Asp Ser Al - #a Leu Val Leu Ser Pro                           1035 - #               1040  - #              1045             - - GCC GCC AGG AAC TGC TCC CTC AGC CAG GAA TG - #T GCC CTG GAC CAA TCT         3222                                                                       Ala Ala Arg Asn Cys Ser Leu Ser Gln Glu Cy - #s Ala Leu Asp Gln Ser                       1050     - #           1055      - #          1060                 - - GTC TAT GCC ATG GTA TTC ACC GTG CTC TGC AG - #C CTG GGT ATC GCG CTG         3270                                                                       Val Tyr Ala Met Val Phe Thr Val Leu Cys Se - #r Leu Gly Ile Ala Leu                   1065         - #       1070          - #      1075                     - - TGC CTT GTC ACC TCT GTC ACT GTG GAG TGG AC - #G GGA CTG AAG GTG GCC         3318                                                                       Cys Leu Val Thr Ser Val Thr Val Glu Trp Th - #r Gly Leu Lys Val Ala               1080             - #   1085              - #  1090                         - - AAG AGG CTG CAT CGC AGC CTG CTC AAC CGT AT - #C ATC CTG GCT CCC ATG         3366                                                                       Lys Arg Leu His Arg Ser Leu Leu Asn Arg Il - #e Ile Leu Ala Pro Met           1095                1100 - #                1105 - #               1110        - - AGG TTC TTT GAG ACC ACG CCC CTG GGG AGT AT - #C CTG AAC AGA TTT TCA         3414                                                                       Arg Phe Phe Glu Thr Thr Pro Leu Gly Ser Il - #e Leu Asn Arg Phe Ser                           1115 - #               1120  - #              1125             - - TCT GAC TGT AAC ACC ATT GAC CAG CAT ATC CC - #G TCC ACG CTG GAG TGC         3462                                                                       Ser Asp Cys Asn Thr Ile Asp Gln His Ile Pr - #o Ser Thr Leu Glu Cys                       1130     - #           1135      - #          1140                 - - CTG AGC AGA TCC ACC TTA CTC TGT GTC TCC GC - #C CTG GCT GTC ATC TCC         3510                                                                       Leu Ser Arg Ser Thr Leu Leu Cys Val Ser Al - #a Leu Ala Val Ile Ser                   1145         - #       1150          - #      1155                     - - TAC GTC ACG CCT GTG TTC CTA GTG GCC CTC TT - #A CCC CTC GCC GTC GTG         3558                                                                       Tyr Val Thr Pro Val Phe Leu Val Ala Leu Le - #u Pro Leu Ala Val Val               1160             - #   1165              - #  1170                         - - TGC TAC TTC ATC CAG AAG TAC TTC CGA GTG GC - #G TCC AGG GAC CTG CAG         3606                                                                       Cys Tyr Phe Ile Gln Lys Tyr Phe Arg Val Al - #a Ser Arg Asp Leu Gln           1175                1180 - #                1185 - #               1190        - - CAG CTG GAC GAC ACA ACA CAG CTC CCT CTG CT - #C TCA CAC TTT GCT GAA         3654                                                                       Gln Leu Asp Asp Thr Thr Gln Leu Pro Leu Le - #u Ser His Phe Ala Glu                           1195 - #               1200  - #              1205             - - ACT GTG GAA GGA CTC ACC ACC ATC CGT GCC TT - #C AGG TAC GAG GCC CGG         3702                                                                       Thr Val Glu Gly Leu Thr Thr Ile Arg Ala Ph - #e Arg Tyr Glu Ala Arg                       1210     - #           1215      - #          1220                 - - TTC CAG CAG AAG CTC CTA GAG TAC ACC GAC TC - #C AAC AAC ATT GCC TCT         3750                                                                       Phe Gln Gln Lys Leu Leu Glu Tyr Thr Asp Se - #r Asn Asn Ile Ala Ser                   1225         - #       1230          - #      1235                     - - CTC TTC CTC ACA GCA GCC AAC AGG TGG CTG GA - #A GTC CGC ATG GAG TAC         3798                                                                       Leu Phe Leu Thr Ala Ala Asn Arg Trp Leu Gl - #u Val Arg Met Glu Tyr               1240             - #   1245              - #  1250                         - - ATC GGA GCA TGC GTG GTA CTC ATC GCC GCT GC - #C ACC TCC ATC TCC AAC         3846                                                                       Ile Gly Ala Cys Val Val Leu Ile Ala Ala Al - #a Thr Ser Ile Ser Asn           1255                1260 - #                1265 - #               1270        - - TCC CTA CAC AGG GAG CTC TCA GCC GGC CTA GT - #A GGC CTG GGC CTC ACC         3894                                                                       Ser Leu His Arg Glu Leu Ser Ala Gly Leu Va - #l Gly Leu Gly Leu Thr                           1275 - #               1280  - #              1285             - - TAT GCC TTG ATG ATT GGG ATC TGC GGC CGC AC - #A GGC AGT GGA AAA TCC         3942                                                                       Tyr Ala Leu Met Ile Gly Ile Cys Gly Arg Th - #r Gly Ser Gly Lys Ser                       1290     - #           1295      - #          1300                 - - TCC TTC TCT CTC GCC TTT TTC CGA ATG GTG GA - #T ATG TTT GAA GGG CGT         3990                                                                       Ser Phe Ser Leu Ala Phe Phe Arg Met Val As - #p Met Phe Glu Gly Arg                   1305         - #       1310          - #      1315                     - - ATC ATC ATC GAT GGC ATT GAC ATC GCC AAG CT - #G CCG CTG CAC ACG CTC         4038                                                                       Ile Ile Ile Asp Gly Ile Asp Ile Ala Lys Le - #u Pro Leu His Thr Leu               1320             - #   1325              - #  1330                         - - CGC TCA CGC CTG TCT ATC ATC CTA CAG GAC CC - #T GTT CTC TTC AGT GGT         4086                                                                       Arg Ser Arg Leu Ser Ile Ile Leu Gln Asp Pr - #o Val Leu Phe Ser Gly           1335                1340 - #                1345 - #               1350        - - ACC ATC AGA TTC AAC CTG GAC CCA GAG AAG AA - #A TGC TCA GAC AGC ACG         4134                                                                       Thr Ile Arg Phe Asn Leu Asp Pro Glu Lys Ly - #s Cys Ser Asp Ser Thr                           1355 - #               1360  - #              1365             - - CTG TGG GAG GCT CTG GAG ATC GCT CAG CTG AA - #G CTG GTG GTG AAG GCC         4182                                                                       Leu Trp Glu Ala Leu Glu Ile Ala Gln Leu Ly - #s Leu Val Val Lys Ala                       1370     - #           1375      - #          1380                 - - CTG CCA GGA GGC CTG GAT GCC ATC ATC ACG GA - #A GGA GGG GAG AAT TTT         4230                                                                       Leu Pro Gly Gly Leu Asp Ala Ile Ile Thr Gl - #u Gly Gly Glu Asn Phe                   1385         - #       1390          - #      1395                     - - AGC CAG GGC CAG AGG CAG CTG TTC TGC CTG GC - #C CGG GCC TTT GTG AGG         4278                                                                       Ser Gln Gly Gln Arg Gln Leu Phe Cys Leu Al - #a Arg Ala Phe Val Arg               1400             - #   1405              - #  1410                         - - AAG ACC AGC ATC TTC ATC ATG GAT GAA GCA AC - #T GCC TCC ATC GAC ATG         4326                                                                       Lys Thr Ser Ile Phe Ile Met Asp Glu Ala Th - #r Ala Ser Ile Asp Met           1415                1420 - #                1425 - #               1430        - - GCT ACG GAA AAT ATC CTC CAG AAG GTG GTG AT - #G ACA GCC TTC GCA GAC         4374                                                                       Ala Thr Glu Asn Ile Leu Gln Lys Val Val Me - #t Thr Ala Phe Ala Asp                           1435 - #               1440  - #              1445             - - CGC ACC GTG GTC ACC ATC GCG CAC CGC GTG CA - #C ACC ATC CTG AGT GCA         4422                                                                       Arg Thr Val Val Thr Ile Ala His Arg Val Hi - #s Thr Ile Leu Ser Ala                       1450     - #           1455      - #          1460                 - - GAC CTA GTG ATG GTC CTG AAG AGG GGC GCG AT - #C CTG GAG TTC GAC AAG         4470                                                                       Asp Leu Val Met Val Leu Lys Arg Gly Ala Il - #e Leu Glu Phe Asp Lys                   1465         - #       1470          - #      1475                     - - CCG GAA AAG CTT CTC AGC CAG AAG GAC AGC GT - #C TTT GCC TCC TTT GTC         4518                                                                       Pro Glu Lys Leu Leu Ser Gln Lys Asp Ser Va - #l Phe Ala Ser Phe Val               1480             - #   1485              - #  1490                         - - CGC GCG GAC AAA TGACCAGCCA GCGCCAAAGT GCCACCCCAC AC - #CTCACCTG             4570                                                                       Arg Ala Asp Lys                                                               1495                                                                           - - CTTGCCATGG ATTTCTTACT GTAAATCACT TGTAAATAAA GAAACTAATT CT -             #TTGCTAAA   4630                                                                 - - AAAAA                 - #                  - #                  -      #          4635                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:28:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1498 amino - #acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                              - - Met Pro Leu Ala Phe Cys Gly Thr Glu Asn Hi - #s Ser Ala Ala Tyr        Arg                                                                               1               5 - #                 10 - #                 15             - - Val Asp Gln Gly Val Leu Asn Asn Gly Cys Ph - #e Val Asp Ala Leu Asn                   20     - #             25     - #             30                  - - Val Val Pro His Val Phe Leu Leu Phe Ile Th - #r Phe Pro Ile Leu Phe               35         - #         40         - #         45                      - - Ile Gly Trp Gly Ser Gln Ser Ser Lys Val Hi - #s Ile His His Ser Thr           50             - #     55             - #     60                          - - Trp Leu His Phe Pro Gly His Asn Leu Arg Tr - #p Ile Leu Thr Phe Ile       65                 - # 70                 - # 75                 - # 80       - - Leu Leu Phe Val Leu Val Cys Glu Ile Ala Gl - #u Gly Ile Leu Ser Asp                       85 - #                 90 - #                 95              - - Gly Val Thr Glu Ser Arg His Leu His Leu Ty - #r Met Pro Ala Gly Met                  100      - #           105      - #           110                  - - Ala Phe Met Ala Ala Ile Thr Ser Val Val Ty - #r Tyr His Asn Ile Glu              115          - #       120          - #       125                      - - Thr Ser Asn Phe Pro Lys Leu Leu Ile Ala Le - #u Leu Ile Tyr Trp Thr          130              - #   135              - #   140                          - - Leu Ala Phe Ile Thr Lys Thr Ile Lys Phe Va - #l Lys Phe Tyr Asp His      145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - Ala Ile Gly Phe Ser Gln Leu Arg Phe Cys Le - #u Thr Gly Leu Leu        Val                                                                                             165  - #               170  - #               175             - - Ile Leu Tyr Gly Met Leu Leu Leu Val Glu Va - #l Asn Val Ile Arg Val                  180      - #           185      - #           190                  - - Arg Arg Tyr Val Phe Phe Lys Thr Pro Arg Gl - #u Val Lys Pro Pro Glu              195          - #       200          - #       205                      - - Asp Leu Gln Asp Leu Gly Val Arg Phe Leu Gl - #n Pro Phe Val Asn Leu          210              - #   215              - #   220                          - - Leu Ser Lys Gly Thr Tyr Trp Trp Met Asn Al - #a Phe Ile Lys Thr Ala      225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - His Lys Lys Pro Ile Asp Leu Arg Ala Ile Gl - #y Lys Leu Pro Ile        Ala                                                                                             245  - #               250  - #               255             - - Met Arg Ala Leu Thr Asn Tyr Gln Arg Leu Cy - #s Leu Ala Phe Asp Ala                  260      - #           265      - #           270                  - - Gln Ala Arg Lys Asp Thr Gln Ser Gln Gln Gl - #y Ala Arg Ala Ile Trp              275          - #       280          - #       285                      - - Arg Ala Leu Cys His Ala Phe Gly Arg Arg Le - #u Val Leu Ser Ser Thr          290              - #   295              - #   300                          - - Phe Arg Ile Leu Ala Asp Leu Leu Gly Phe Al - #a Gly Pro Leu Cys Ile      305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - Phe Gly Ile Val Asp His Leu Gly Lys Glu As - #n His Val Phe Gln        Pro                                                                                             325  - #               330  - #               335             - - Lys Thr Gln Phe Leu Gly Val Tyr Phe Val Se - #r Ser Gln Glu Phe Leu                  340      - #           345      - #           350                  - - Gly Asn Ala Tyr Val Leu Ala Val Leu Leu Ph - #e Leu Ala Leu Leu Leu              355          - #       360          - #       365                      - - Gln Arg Thr Phe Leu Gln Ala Ser Tyr Tyr Va - #l Ala Ile Glu Thr Gly          370              - #   375              - #   380                          - - Ile Asn Leu Arg Gly Ala Ile Gln Thr Lys Il - #e Tyr Asn Lys Ile Met      385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - His Leu Ser Thr Ser Asn Leu Ser Met Gly Gl - #u Met Thr Ala Gly        Gln                                                                                             405  - #               410  - #               415             - - Ile Cys Asn Leu Val Ala Ile Asp Thr Asn Gl - #n Leu Met Trp Phe Phe                  420      - #           425      - #           430                  - - Phe Leu Cys Pro Asn Leu Trp Ala Met Pro Va - #l Gln Ile Ile Val Gly              435          - #       440          - #       445                      - - Val Ile Leu Leu Tyr Tyr Ile Leu Gly Val Se - #r Ala Leu Ile Gly Ala          450              - #   455              - #   460                          - - Ala Val Ile Ile Leu Leu Ala Pro Val Gln Ty - #r Phe Val Ala Thr Lys      465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - Leu Ser Gln Ala Gln Arg Thr Thr Leu Glu Ty - #r Ser Asn Glu Arg        Leu                                                                                             485  - #               490  - #               495             - - Lys Gln Thr Asn Glu Met Leu Arg Gly Ile Ly - #s Leu Leu Lys Leu Tyr                  500      - #           505      - #           510                  - - Ala Trp Glu Asn Ile Phe Cys Ser Arg Val Gl - #u Lys Thr Arg Arg Lys              515          - #       520          - #       525                      - - Glu Met Thr Ser Leu Arg Ala Phe Ala Val Ty - #r Thr Ser Ile Ser Ile          530              - #   535              - #   540                          - - Phe Met Asn Thr Ala Ile Pro Ile Ala Ala Va - #l Leu Ile Thr Phe Val      545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - Gly His Val Ser Phe Phe Lys Glu Ser Asp Ph - #e Ser Pro Ser Val        Ala                                                                                             565  - #               570  - #               575             - - Phe Ala Ser Leu Ser Leu Phe His Ile Leu Va - #l Thr Pro Leu Phe Leu                  580      - #           585      - #           590                  - - Leu Ser Ser Val Val Arg Ser Thr Val Lys Al - #a Leu Val Ser Val Gln              595          - #       600          - #       605                      - - Lys Leu Ser Glu Phe Leu Ser Ser Ala Glu Il - #e Arg Glu Glu Gln Cys          610              - #   615              - #   620                          - - Ala Pro Arg Glu Pro Ala Pro Gln Gly Gln Al - #a Gly Lys Tyr Gln Ala      625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - Val Pro Leu Lys Val Val Asn Arg Lys Arg Pr - #o Ala Arg Glu Glu        Val                                                                                             645  - #               650  - #               655             - - Arg Asp Leu Leu Gly Pro Leu Gln Arg Leu Th - #r Pro Ser Thr Asp Gly                  660      - #           665      - #           670                  - - Asp Ala Asp Asn Phe Cys Val Gln Ile Ile Gl - #y Gly Phe Phe Thr Trp              675          - #       680          - #       685                      - - Thr Pro Asp Gly Ile Pro Thr Leu Ser Asn Il - #e Thr Ile Arg Ile Pro          690              - #   695              - #   700                          - - Arg Gly Gln Leu Thr Met Ile Val Gly Gln Va - #l Gly Cys Gly Lys Ser      705                 7 - #10                 7 - #15                 7 -      #20                                                                              - - Ser Leu Leu Leu Ala Thr Leu Gly Glu Met Gl - #n Lys Val Ser Gly        Ala                                                                                             725  - #               730  - #               735             - - Val Phe Trp Asn Ser Leu Pro Asp Ser Glu Gl - #y Arg Arg Pro Gln Gln                  740      - #           745      - #           750                  - - Pro Arg Ala Gly Asp Ser Gly Arg Phe Gly Cy - #s Gln Glu Gln Arg Pro              755          - #       760          - #       765                      - - Cys Gly Tyr Ala Ser Gln Lys Pro Trp Leu Le - #u Asn Ala Thr Val Glu          770              - #   775              - #   780                          - - Glu Asn Ile Thr Phe Glu Ser Pro Phe Asn Ly - #s Gln Arg Tyr Lys Met      785                 7 - #90                 7 - #95                 8 -      #00                                                                              - - Val Ile Glu Ala Cys Ser Leu Gln Pro Asp Il - #e Asp Ile Leu Pro        His                                                                                             805  - #               810  - #               815             - - Gly Asp Gln Thr Gln Ile Gly Glu Arg Gly Il - #e Asn Leu Ser Thr Gly                  820      - #           825      - #           830                  - - Gly Gln Arg Pro Asp Gln Cys Arg Pro Glu Pr - #o Ser Thr Ser Thr Pro              835          - #       840          - #       845                      - - Met Ile Val Phe Leu Asp Asp Pro Phe Ser Al - #a Leu Asp Val His Leu          850              - #   855              - #   860                          - - Ser Asp His Leu Met Gln Ala Gly Ile Leu Gl - #u Leu Leu Arg Asp Asp      865                 8 - #70                 8 - #75                 8 -      #80                                                                              - - Lys Arg Thr Val Val Leu Val Thr His Lys Le - #u Gln Tyr Leu Pro        His                                                                                             885  - #               890  - #               895             - - Ala Asp Trp Ile Ile Ala Met Lys Asp Gly Th - #r Ile Gln Arg Glu Gly                  900      - #           905      - #           910                  - - Thr Leu Lys Asp Phe Gln Arg Ser Glu Cys Gl - #n Leu Phe Glu His Trp              915          - #       920          - #       925                      - - Lys Thr Leu Met Asn Arg Gln Asp Gln Glu Le - #u Glu Lys Glu Thr Val          930              - #   935              - #   940                          - - Met Glu Arg Lys Ala Pro Glu Pro Ser Gln Gl - #y Leu Pro Arg Ala Met      945                 9 - #50                 9 - #55                 9 -      #60                                                                              - - Ser Ser Arg Asp Gly Leu Leu Leu Asp Glu As - #p Glu Glu Glu Glu        Glu                                                                                             965  - #               970  - #               975             - - Ala Ala Glu Ser Glu Glu Asp Asp Asn Leu Se - #r Ser Val Leu His Gln                  980      - #           985      - #           990                  - - Arg Ala Lys Ile Pro Trp Arg Ala Cys Thr Ly - #s Tyr Leu Ser Ser Ala              995          - #       1000          - #      1005                     - - Gly Ile Leu Leu Leu Ser Leu Leu Val Phe Se - #r Gln Leu Leu Lys His          1010             - #   1015              - #  1020                         - - Met Val Leu Val Ala Ile Asp Tyr Trp Leu Al - #a Lys Trp Thr Asp Ser      1025                1030 - #                1035 - #               1040        - - Ala Leu Val Leu Ser Pro Ala Ala Arg Asn Cy - #s Ser Leu Ser Gln Glu                      1045 - #               1050  - #              1055             - - Cys Ala Leu Asp Gln Ser Val Tyr Ala Met Va - #l Phe Thr Val Leu Cys                  1060     - #           1065      - #          1070                 - - Ser Leu Gly Ile Ala Leu Cys Leu Val Thr Se - #r Val Thr Val Glu Trp              1075         - #       1080          - #      1085                     - - Thr Gly Leu Lys Val Ala Lys Arg Leu His Ar - #g Ser Leu Leu Asn Arg          1090             - #   1095              - #  1100                         - - Ile Ile Leu Ala Pro Met Arg Phe Phe Glu Th - #r Thr Pro Leu Gly Ser      1105                1110 - #                1115 - #               1120        - - Ile Leu Asn Arg Phe Ser Ser Asp Cys Asn Th - #r Ile Asp Gln His Ile                      1125 - #               1130  - #              1135             - - Pro Ser Thr Leu Glu Cys Leu Ser Arg Ser Th - #r Leu Leu Cys Val Ser                  1140     - #           1145      - #          1150                 - - Ala Leu Ala Val Ile Ser Tyr Val Thr Pro Va - #l Phe Leu Val Ala Leu              1155         - #       1160          - #      1165                     - - Leu Pro Leu Ala Val Val Cys Tyr Phe Ile Gl - #n Lys Tyr Phe Arg Val          1170             - #   1175              - #  1180                         - - Ala Ser Arg Asp Leu Gln Gln Leu Asp Asp Th - #r Thr Gln Leu Pro Leu      1185                1190 - #                1195 - #               1200        - - Leu Ser His Phe Ala Glu Thr Val Glu Gly Le - #u Thr Thr Ile Arg Ala                      1205 - #               1210  - #              1215             - - Phe Arg Tyr Glu Ala Arg Phe Gln Gln Lys Le - #u Leu Glu Tyr Thr Asp                  1220     - #           1225      - #          1230                 - - Ser Asn Asn Ile Ala Ser Leu Phe Leu Thr Al - #a Ala Asn Arg Trp Leu              1235         - #       1240          - #      1245                     - - Glu Val Arg Met Glu Tyr Ile Gly Ala Cys Va - #l Val Leu Ile Ala Ala          1250             - #   1255              - #  1260                         - - Ala Thr Ser Ile Ser Asn Ser Leu His Arg Gl - #u Leu Ser Ala Gly Leu      1265                1270 - #                1275 - #               1280        - - Val Gly Leu Gly Leu Thr Tyr Ala Leu Met Il - #e Gly Ile Cys Gly Arg                      1285 - #               1290  - #              1295             - - Thr Gly Ser Gly Lys Ser Ser Phe Ser Leu Al - #a Phe Phe Arg Met Val                  1300     - #           1305      - #          1310                 - - Asp Met Phe Glu Gly Arg Ile Ile Ile Asp Gl - #y Ile Asp Ile Ala Lys              1315         - #       1320          - #      1325                     - - Leu Pro Leu His Thr Leu Arg Ser Arg Leu Se - #r Ile Ile Leu Gln Asp          1330             - #   1335              - #  1340                         - - Pro Val Leu Phe Ser Gly Thr Ile Arg Phe As - #n Leu Asp Pro Glu Lys      1345                1350 - #                1355 - #               1360        - - Lys Cys Ser Asp Ser Thr Leu Trp Glu Ala Le - #u Glu Ile Ala Gln Leu                      1365 - #               1370  - #              1375             - - Lys Leu Val Val Lys Ala Leu Pro Gly Gly Le - #u Asp Ala Ile Ile Thr                  1380     - #           1385      - #          1390                 - - Glu Gly Gly Glu Asn Phe Ser Gln Gly Gln Ar - #g Gln Leu Phe Cys Leu              1395         - #       1400          - #      1405                     - - Ala Arg Ala Phe Val Arg Lys Thr Ser Ile Ph - #e Ile Met Asp Glu Ala          1410             - #   1415              - #  1420                         - - Thr Ala Ser Ile Asp Met Ala Thr Glu Asn Il - #e Leu Gln Lys Val Val      1425                1430 - #                1435 - #               1440        - - Met Thr Ala Phe Ala Asp Arg Thr Val Val Th - #r Ile Ala His Arg Val                      1445 - #               1450  - #              1455             - - His Thr Ile Leu Ser Ala Asp Leu Val Met Va - #l Leu Lys Arg Gly Ala                  1460     - #           1465      - #          1470                 - - Ile Leu Glu Phe Asp Lys Pro Glu Lys Leu Le - #u Ser Gln Lys Asp Ser              1475         - #       1480          - #      1485                     - - Val Phe Ala Ser Phe Val Arg Ala Asp Lys                                      1490             - #   1495                                                - -  - - (2) INFORMATION FOR SEQ ID NO:29:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1498 amino - #acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                              - - Met Pro Leu Ala Phe Cys Gly Thr Glu Asn Hi - #s Ser Ala Ala Tyr Arg        1               5 - #                 10 - #                 15              - - Val Asp Gln Gly Val Leu Asn Asn Gly Cys Ph - #e Val Asp Ala Leu Asn                   20     - #             25     - #             30                  - - Val Val Pro His Val Phe Leu Leu Phe Ile Th - #r Phe Pro Ile Leu Phe               35         - #         40         - #         45                      - - Ile Gly Trp Gly Ser Gln Ser Ser Lys Val Hi - #s Ile His His Ser Thr           50             - #     55             - #     60                          - - Trp Leu His Phe Pro Gly His Asn Leu Arg Tr - #p Ile Leu Thr Phe Ile       65                 - # 70                 - # 75                 - # 80       - - Leu Leu Phe Val Leu Val Cys Glu Ile Ala Gl - #u Gly Ile Leu Ser Asp                       85 - #                 90 - #                 95              - - Gly Val Thr Glu Ser Arg His Leu His Leu Ty - #r Met Pro Ala Gly Met                  100      - #           105      - #           110                  - - Ala Phe Met Ala Ala Ile Thr Ser Val Val Ty - #r Tyr His Asn Ile Glu              115          - #       120          - #       125                      - - Thr Ser Asn Phe Pro Lys Leu Leu Ile Ala Le - #u Leu Ile Tyr Trp Thr          130              - #   135              - #   140                          - - Leu Ala Phe Ile Thr Lys Thr Ile Lys Phe Va - #l Lys Phe Tyr Asp His      145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - Ala Ile Gly Phe Ser Gln Leu Arg Phe Cys Le - #u Thr Gly Leu Leu        Val                                                                                             165  - #               170  - #               175             - - Ile Leu Tyr Gly Met Leu Leu Leu Val Glu Va - #l Asn Val Ile Arg Val                  180      - #           185      - #           190                  - - Arg Arg Tyr Ile Phe Phe Lys Thr Pro Arg Gl - #u Val Lys Pro Pro Glu              195          - #       200          - #       205                      - - Asp Leu Gln Asp Leu Gly Val Arg Phe Leu Gl - #n Pro Phe Val Asn Leu          210              - #   215              - #   220                          - - Leu Ser Lys Gly Thr Tyr Trp Trp Met Asn Al - #a Phe Ile Lys Thr Ala      225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - His Lys Lys Pro Ile Asp Leu Arg Ala Ile Al - #a Lys Leu Pro Ile        Ala                                                                                             245  - #               250  - #               255             - - Met Arg Ala Leu Thr Asn Tyr Gln Arg Leu Cy - #s Val Ala Phe Asp Ala                  260      - #           265      - #           270                  - - Gln Ala Arg Lys Asp Thr Gln Ser Pro Gln Gl - #y Ala Arg Ala Ile Trp              275          - #       280          - #       285                      - - Arg Ala Leu Cys His Ala Phe Gly Arg Arg Le - #u Ile Leu Ser Ser Thr          290              - #   295              - #   300                          - - Phe Arg Ile Leu Ala Asp Leu Leu Gly Phe Al - #a Gly Pro Leu Cys Ile      305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - Phe Gly Ile Val Asp His Leu Gly Lys Glu As - #n His Val Phe Gln        Pro                                                                                             325  - #               330  - #               335             - - Lys Thr Gln Phe Leu Gly Val Tyr Phe Val Se - #r Ser Gln Glu Phe Leu                  340      - #           345      - #           350                  - - Gly Asn Ala Tyr Val Leu Ala Val Leu Leu Ph - #e Leu Ala Leu Leu Leu              355          - #       360          - #       365                      - - Gln Arg Thr Phe Leu Gln Ala Ser Tyr Tyr Va - #l Ala Ile Glu Thr Gly          370              - #   375              - #   380                          - - Ile Asn Leu Arg Gly Ala Ile Gln Thr Lys Il - #e Tyr Asn Lys Ile Met      385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - His Met Ser Thr Ser Asn Leu Ser Met Gly Gl - #u Met Thr Ala Gly        Gln                                                                                             405  - #               410  - #               415             - - Ile Cys Asn Leu Val Ala Ile Asp Thr Asn Gl - #n Leu Met Trp Phe Phe                  420      - #           425      - #           430                  - - Phe Leu Cys Pro Asn Leu Trp Thr Met Pro Va - #l Gln Ile Ile Val Gly              435          - #       440          - #       445                      - - Val Ile Leu Leu Tyr Tyr Ile Leu Gly Val Se - #r Ala Leu Ile Gly Ala          450              - #   455              - #   460                          - - Ala Val Ile Ile Leu Leu Ala Pro Val Gln Ty - #r Phe Val Ala Thr Lys      465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - Leu Ser Gln Ala Gln Arg Thr Thr Leu Glu Hi - #s Ser Asn Glu Arg        Leu                                                                                             485  - #               490  - #               495             - - Lys Gln Thr Asn Glu Met Leu Arg Gly Met Ly - #s Leu Leu Lys Leu Tyr                  500      - #           505      - #           510                  - - Ala Trp Glu Ser Ile Phe Cys Ser Arg Val Gl - #u Val Thr Arg Arg Lys              515          - #       520          - #       525                      - - Glu Met Thr Ser Leu Arg Ala Phe Ala Val Ty - #r Thr Ser Ile Ser Ile          530              - #   535              - #   540                          - - Phe Met Asn Thr Ala Ile Pro Ile Ala Ala Va - #l Leu Ile Thr Phe Val      545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - Gly His Val Ser Phe Phe Lys Glu Ser Asp Le - #u Ser Pro Ser Val        Ala                                                                                             565  - #               570  - #               575             - - Phe Ala Ser Leu Ser Leu Phe His Ile Leu Va - #l Thr Pro Leu Phe Leu                  580      - #           585      - #           590                  - - Leu Ser Ser Val Val Arg Ser Thr Val Lys Al - #a Leu Val Ser Val Gln              595          - #       600          - #       605                      - - Lys Leu Ser Glu Phe Leu Ser Ser Ala Glu Il - #e Arg Glu Glu Gln Cys          610              - #   615              - #   620                          - - Ala Pro Arg Glu Pro Ala Pro Gln Gly Gln Al - #a Gly Lys Tyr Gln Ala      625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - Val Pro Leu Lys Val Val Asn Arg Lys Arg Pr - #o Ala Arg Glu Glu        Val                                                                                             645  - #               650  - #               655             - - Arg Asp Leu Leu Gly Pro Leu Gln Arg Leu Al - #a Pro Ser Met Asp Gly                  660      - #           665      - #           670                  - - Asp Ala Asp Asn Phe Cys Val Gln Ile Ile Gl - #y Gly Phe Phe Thr Trp              675          - #       680          - #       685                      - - Thr Pro Asp Gly Ile Pro Thr Leu Ser Asn Il - #e Thr Ile Arg Ile Pro          690              - #   695              - #   700                          - - Arg Gly Gln Leu Thr Met Ile Val Gly Gln Va - #l Gly Cys Gly Lys Ser      705                 7 - #10                 7 - #15                 7 -      #20                                                                              - - Ser Leu Leu Leu Ala Thr Leu Gly Glu Met Gl - #n Lys Val Ser Gly        Ala                                                                                             725  - #               730  - #               735             - - Val Phe Trp Asn Ser Asn Leu Pro Asp Ser Gl - #u Gly Arg Gly Pro Gln                  740      - #           745      - #           750                  - - Gln Pro Arg Ala Gly Asp Ser Ser Trp Leu Gl - #y Tyr Gln Glu Gln Arg              755          - #       760          - #       765                      - - Pro Arg Gly Tyr Ala Ser Gln Lys Pro Trp Le - #u Leu Asn Ala Thr Val          770              - #   775              - #   780                          - - Glu Glu Asn Ile Thr Phe Glu Ser Pro Phe As - #n Pro Gln Arg Tyr Lys      785                 7 - #90                 7 - #95                 8 -      #00                                                                              - - Met Val Ile Glu Ala Cys Ser Leu Gln Pro As - #p Ile Asp Ile Leu        Pro                                                                                             805  - #               810  - #               815             - - His Gly Asp Gln Thr Gln Ile Gly Glu Arg Gl - #y Ile Asn Leu Ser Gly                  820      - #           825      - #           830                  - - Gly Gln Arg Pro Asp Gln Cys Gly Pro Glu Pr - #o Ser Thr Ser Arg Pro              835          - #       840          - #       845                      - - Met Phe Val Phe Leu Asp Asp Pro Phe Ser Al - #a Leu Asp Val His Leu          850              - #   855              - #   860                          - - Ser Asp His Leu Met Gln Ala Gly Ile Leu Gl - #u Leu Leu Arg Asp Asp      865                 8 - #70                 8 - #75                 8 -      #80                                                                              - - Lys Arg Thr Val Val Leu Val Thr His Lys Le - #u Gln Tyr Leu Pro        His                                                                                             885  - #               890  - #               895             - - Ala Asp Trp Ile Ile Ala Met Lys Asp Gly Th - #r Ile Gln Arg Glu Gly                  900      - #           905      - #           910                  - - Thr Leu Lys Asp Phe Gln Arg Ser Glu Cys Gl - #n Leu Phe Glu His Trp              915          - #       920          - #       925                      - - Lys Thr Leu Met Asn Arg Gln Asp Gln Glu Le - #u Glu Lys Glu Thr Val          930              - #   935              - #   940                          - - Met Glu Arg Lys Ala Ser Glu Pro Ser Gln Gl - #y Leu Pro Arg Ala Met      945                 9 - #50                 9 - #55                 9 -      #60                                                                              - - Ser Ser Arg Asp Gly Leu Leu Leu Asp Glu Gl - #u Glu Glu Glu Glu        Glu                                                                                             965  - #               970  - #               975             - - Ala Ala Glu Ser Glu Glu Asp Asp Asn Leu Se - #r Ser Val Leu His Gln                  980      - #           985      - #           990                  - - Arg Ala Lys Ile Pro Trp Arg Ala Cys Thr Ly - #s Tyr Leu Ser Ser Ala              995          - #       1000          - #      1005                     - - Gly Ile Leu Leu Leu Ser Leu Leu Val Phe Se - #r Gln Leu Leu Lys His          1010             - #   1015              - #  1020                         - - Met Val Leu Val Ala Ile Asp Tyr Trp Leu Al - #a Lys Trp Thr Asp Ser      1025                1030 - #                1035 - #               1040        - - Ala Leu Val Leu Ser Pro Ala Ala Arg Asn Cy - #s Ser Leu Ser Gln Glu                      1045 - #               1050  - #              1055             - - Cys Asp Leu Asp Gln Ser Val Tyr Ala Met Va - #l Phe Thr Leu Leu Cys                  1060     - #           1065      - #          1070                 - - Ser Leu Gly Ile Val Leu Cys Leu Val Thr Se - #r Val Thr Val Glu Trp              1075         - #       1080          - #      1085                     - - Thr Gly Leu Lys Val Ala Lys Arg Leu His Ar - #g Ser Leu Leu Asn Arg          1090             - #   1095              - #  1100                         - - Ile Ile Leu Ala Pro Met Arg Phe Phe Glu Th - #r Thr Pro Leu Gly Ser      1105                1110 - #                1115 - #               1120        - - Ile Leu Asn Arg Phe Ser Ser Asp Cys Asn Th - #r Ile Asp Gln His Ile                      1125 - #               1130  - #              1135             - - Pro Ser Thr Leu Glu Cys Leu Ser Arg Ser Th - #r Leu Leu Cys Val Ser                  1140     - #           1145      - #          1150                 - - Ala Leu Thr Val Ile Ser Tyr Val Thr Pro Va - #l Phe Leu Val Ala Leu              1155         - #       1160          - #      1165                     - - Leu Pro Leu Ala Val Val Cys Tyr Phe Ile Gl - #n Lys Tyr Phe Arg Val          1170             - #   1175              - #  1180                         - - Ala Ser Arg Asp Leu Gln Gln Leu Asp Asp Th - #r Thr Gln Leu Pro Leu      1185                1190 - #                1195 - #               1200        - - Val Ser His Phe Ala Glu Thr Val Glu Gly Le - #u Thr Thr Ile Arg Ala                      1205 - #               1210  - #              1215             - - Phe Arg Tyr Glu Ala Arg Phe Gln Gln Lys Le - #u Leu Glu Tyr Thr Asp                  1220     - #           1225      - #          1230                 - - Ser Asn Asn Ile Ala Ser Leu Phe Leu Thr Al - #a Ala Asn Arg Trp Leu              1235         - #       1240          - #      1245                     - - Glu Val Cys Met Glu Tyr Ile Gly Ala Cys Va - #l Val Leu Ile Ala Ala          1250             - #   1255              - #  1260                         - - Ala Thr Ser Ile Ser Asn Ser Leu His Arg Gl - #u Leu Ser Ala Gly Leu      1265                1270 - #                1275 - #               1280        - - Val Gly Leu Gly Leu Thr Tyr Ala Leu Met Il - #e Gly Ile Cys Gly Arg                      1285 - #               1290  - #              1295             - - Thr Ala Ser Gly Lys Ser Ser Phe Ser Leu Al - #a Phe Phe Arg Met Val                  1300     - #           1305      - #          1310                 - - Asp Met Phe Glu Gly Arg Ile Ile Ile Asp Gl - #y Ile Asp Ile Ala Lys              1315         - #       1320          - #      1325                     - - Leu Pro Leu His Thr Leu Arg Ser Arg Leu Se - #r Ile Ile Leu Gln Asp          1330             - #   1335              - #  1340                         - - Pro Val Leu Phe Ser Gly Thr Ile Arg Phe As - #n Leu Asp Pro Glu Lys      1345                1350 - #                1355 - #               1360        - - Lys Cys Ser Asp Ser Thr Leu Trp Glu Ala Le - #u Glu Ile Ala Gln Leu                      1365 - #               1370  - #              1375             - - Lys Leu Val Val Lys Ala Leu Pro Gly Gly Le - #u Asp Ala Ile Ile Thr                  1380     - #           1385      - #          1390                 - - Glu Gly Gly Glu Asn Phe Ser Gln Gly Gln Ar - #g Gln Leu Phe Cys Leu              1395         - #       1400          - #      1405                     - - Ala Arg Ala Phe Val Arg Lys Thr Ser Ile Ph - #e Ile Met Asp Glu Ala          1410             - #   1415              - #  1420                         - - Thr Ala Ser Ile Asp Met Ala Thr Glu Asn Il - #e Leu Gln Lys Val Val      1425                1430 - #                1435 - #               1440        - - Met Thr Ala Phe Ala Asp Arg Thr Val Val Th - #r Ile Ala His Arg Val                      1445 - #               1450  - #              1455             - - His Thr Ile Leu Ser Ala Asp Leu Val Met Va - #l Leu Lys Arg Gly Ala                  1460     - #           1465      - #          1470                 - - Ile Leu Glu Phe Asp Lys Pro Glu Thr Leu Le - #u Ser Gln Lys Asp Ser              1475         - #       1480          - #      1485                     - - Val Phe Ala Ser Phe Val Arg Ala Asp Lys                                      1490             - #   1495                                                - -  - - (2) INFORMATION FOR SEQ ID NO:30:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 2294 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                              - - GATGACCCCT TCTCAGCTTT GGATGTCCAT CTGAGTGACC ACCTGATGCA GG -             #CCGGCATC     60                                                                 - - CTTGAGCTGC TCCGGGATGA CAAGAGGACA GTGGTCTTGG TGACCCACAA GC -            #TACAGTAT    120                                                                 - - CTGCCTCATG CAGACTGGAT CATTGCCATG AAGGATGGGA CCATTCAGAG GG -            #AAGGGACG    180                                                                 - - CTCAAGGACT TCCAGAGGTC CGAGTGCCAG CTCTTTGAGC ACTGGAAGAC CC -            #TCATGAAC    240                                                                 - - CGGCAGGACC AAGAGCTGGA GAAGGAGACA GTCATGGAGA GGAAAGCCTC AG -            #AGCCATCT    300                                                                 - - CAGGGCCTGC CCCGTGCCAT GTCCTCCAGA GACGGCCTTC TGCTGGATGA GG -            #AAGAGGAG    360                                                                 - - GAAGAGGAGG CAGCCGAAAG CGAGGAAGAT GACAACTTAT CTTCAGTGCT GC -            #ATCAGCGA    420                                                                 - - GCTAAGATCC CCTGGCGAGC CTGCACTAAG TATCTGTCCT CTGCTGGCAT TC -            #TGCTCCTG    480                                                                 - - TCCCTGCTTG TCTTCTCCCA GCTGCTCAAG CACATGGTCT TGGTGGCCAT TG -            #ATTATTGG    540                                                                 - - CTGGCCAAGT GGACGGACAG TGCCCTGGTC CTGAGCCCCG CTGCCAGGAA CT -            #GTTCGCTC    600                                                                 - - AGCCAGGAAT GTGACCTGGA CCAGTCTGTC TATGCCATGG TATTCACCTT GC -            #TCTGCAGC    660                                                                 - - CTGGGTATCG TGCTGTGCCT GGTCACCTCT GTCACTGTGG AGTGGACGGG AC -            #TGAAGGTG    720                                                                 - - GCCAAGAGGC TACACCGCAG CCTGCTCAAC CGCATCATCC TGGCCCCCAT GA -            #GGTTCTTT    780                                                                 - - GAGACCACAC CCCTCGGGAG TATCCTGAAC AGATTTTCAT CCGACTGTAA CA -            #CCATTGAC    840                                                                 - - CAGCACATCC CATCCACGCT GGAGTGTCTG AGCCGGTCCA CCCTGCTGTG TG -            #TCTCCGCC    900                                                                 - - CTGACTGTCA TCTCCTATGT CACACCCGTG TTCCTCGTGG CCCTCTTACC CC -            #TAGCTGTT    960                                                                 - - GTGTGCTACT TCATTCAGAA GTACTTCCGA GTGGCATCCA GGGACCTGCA GC -            #AGCTGGAC   1020                                                                 - - GACACGACGC AGCTCCCGCT CGTCTCACAC TTTGCTGAAA CTGTGGAGGG AC -            #TCACCACC   1080                                                                 - - ATCCGTGCCT TCAGGTACGA GGCCCGGTTC CAGCAGAAGC TTCTAGAATA TA -            #CCGACTCC   1140                                                                 - - AACAACATCG CCTCCCTCTT CCTCACGGCA GCCAACAGAT GGCTGGAAGT CT -            #GCATGGAG   1200                                                                 - - TACATCGGAG CGTGCGTGGT ACTCATTGCG GCTGCCACCT CCATCTCCAA CT -            #CCCTGCAC   1260                                                                 - - AGGGAACTTT CTGCTGGCCT GGTGGGCCTG GGCCTCACCT ATGCCTTGAT GG -            #TCTCCAAC   1320                                                                 - - TACCTCAACT GGATGGTGAG GAACCTGGCG GACATGGAGA TCCAGCTGGG GG -            #CTGTGAAG   1380                                                                 - - AGGATCCACG CACTCCTGAA AACCGAGGCG GAGAGCTATG AGGGGCTCCT GG -            #CGCCGTCG   1440                                                                 - - TTGATCCCCA AGAACTGGCC AGACCAAGGG AAGATCCAAA TTCAGAACCT GA -            #GCGTGCGC   1500                                                                 - - TATGACAGCT CCCTGAAGCC AGTGCTGAAG CATGTCAACA CCCTCATCTC CC -            #CGGGGCAG   1560                                                                 - - AAGATCGGGA TCTGCGGCCG CACAGGCAGC GGGAAGTCCT CCTTCTCCCT GG -            #CCTTTTTC   1620                                                                 - - CGAATGGTGG ACATGTTTGA AGGACGCATC ATCATTGATG GCATCGACAT CG -            #CCAAGCTG   1680                                                                 - - CCACTTCACA CGCTGCGCTC ACGCCTGTCC ATCATCCTAC AGGACCCCGT CC -            #TCTTCAGC   1740                                                                 - - GGCACGATCA GATTCAACCT GGACCCCGAG AAGAAATGCT CAGACAGCAC AC -            #TGTGGGAG   1800                                                                 - - GCCCTGGAGA TCGCCCAGCT GAAGCTGGTA GTGAAGGCAC TGCCAGGAGG CC -            #TAGATGCC   1860                                                                 - - ATCATCACAG AAGGAGGGGA GAATTTTAGC CAGGGCCAGA GGCAGCTGTT CT -            #GCCTGGCC   1920                                                                 - - CGGGCCTTCG TGAGGAAGAC CAGCATCTTC ATCATGGATG AAGCAACCGC CT -            #CCATCGAC   1980                                                                 - - ATGGCTACGG AGAACATCCT CCAGAAGGTG GTGATGACAG CCTTCGCAGA CC -            #GCACGGTG   2040                                                                 - - GTCACCATCG CGCATCGTGT GCACACCATC CTGAGTGCAG ACCTGGTGAT GG -            #TCCTCAAG   2100                                                                 - - AGGGGTGCTA TCCTGGAGTT TGACAAGCCA GAGACGCTCC TCAGCCAGAA GG -            #ACAGCGTG   2160                                                                 - - TTCGCCTCCT TTGTCCGTGC GGACAAGTGA CTTACCGGAG CCAAAGTGCC AC -            #CCCGCGCC   2220                                                                 - - TCGCTTGCTT GCCTAGGATT TCTAACTGCA AATCACTTGT AAATAAATTA AT -            #TCTTTGCT   2280                                                                 - - AAAAAAAAAA AAAA              - #                  - #                      - #   2294                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:31:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 195 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                              - - CCATGCCTGG TGGCTGAGCC CAGCCCAGCC CCCAGCACCA TCGCTGATCC CA -             #AAGAACTG     60                                                                 - - GCCAGACCAA GGGAAGATCC AGATCCAGAA CCTGAGCGTG CGCTACGACA GC -            #TCCCTGAA    120                                                                 - - GCCGGTGCTG AAGCACGTCA ATGCCCTCAT CTCCCCTGGA CAGAAGGTCA GT -            #GCACGGGC    180                                                                 - - CCAACCCAAT GCTGC              - #                  - #                      - #   195                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:32:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 2454 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                              - - CTGCTCTCTG CAGCCAGACA TCGACATCCT GCCCCATGGA GACCAGACCC AG -             #ATTGGGGA     60                                                                 - - ACGGGGCATC AACCTGTCTG GTGGTCAACG CCAGCGAATC AGTGTGGCCC GA -            #GCCCTCTA    120                                                                 - - CCAGCACGCC AACGTTGTCT TCTTGGATGA CCCCTTCTCA GCTCTGGATA TC -            #CATCTGAG    180                                                                 - - TGACCACTTA ATGCAGGCCG GCATCCTTGA GCTGCTCCGG GACGACAAGA GG -            #ACAGTGGT    240                                                                 - - CTTAGTGACC CACAAGCTAC AGTACCTGCC CCATGCAGAC TGGATCATTG CC -            #ATGAAGGA    300                                                                 - - TGGCACCATC CAGAGGGAGG GTACCCTCAA GGACTTCCAG AGGTCTGAAT GC -            #CAGCTCTT    360                                                                 - - TGAGCACTGG AAGACCCTCA TGAACCGACA GGACCAAGAG CTGGAGAAGG AG -            #ACTGTCAC    420                                                                 - - AGAGAGAAAA GCCACAGAGC CACCCCAGGG CCTATCTCGT GCCATGTCCT CG -            #AGGGATGG    480                                                                 - - CCTTCTGCAG GATGAGGAAG AGGAGGAAGA GGAGGCAGCT GAGAGCGAGG AG -            #GATGACAA    540                                                                 - - CCTGTCGTCC ATGCTGCACC AGCGTGCTGA GATCCCATGG CGAGCCTGCG CC -            #AAGTACCT    600                                                                 - - GTCCTCCGCC GGCATCCTGC TCCTGTCGTT GCTGGTCTTC TCACAGCTGC TC -            #AAGCACAT    660                                                                 - - GGTCCTGGTG GCCATCGACT ACTGGCTGGC CAAGTGGACC GACAGCGCCC TG -            #ACCCTGAC    720                                                                 - - CCCTGCAGCC AGGAACTGCT CCCTCAGCCA GGAGTGCACC CTCGACCAGA CT -            #GTCTATGC    780                                                                 - - CATGGTGTTC ACGGTGCTCT GCAGCCTGGG CATTGTGCTG TGCCTCGTCA CG -            #TCTGTCAC    840                                                                 - - TGTGGAGTGG ACAGGGCTGA AGGTGGCCAA GAGACTGCAC CGCAGCCTGC TA -            #AACCGGAT    900                                                                 - - CATCCTAGCC CCCATGAGGT TTTTTGAGAC CACTCCCCTT GGGAGCATCC TG -            #AACAGATT    960                                                                 - - TTCATCTGAC TGTAACACCA TCGACCAGCA CATCCCATCC ACGCTGGAGT GC -            #CTGAGCCG   1020                                                                 - - CTCCACCCTG CTCTGTGTCT CAGCCCTGGC CGTCATCTCC TATGTCACAC CT -            #GTGTTCCT   1080                                                                 - - CGTGGCCCTC CTTCCCCTGG CCATCGTGTG CTACTTCATC CAGAAGTACT TC -            #CGGGTGGC   1140                                                                 - - GTCCAGGGAC CTGCAGCAGC TGGATGACAC CACCCAGCTT CCACTTCTCT CA -            #CACTTTGC   1200                                                                 - - CGAAACCGTA GAAGGACTCA CCACCATCCG GGCCTTCAGG TATGAGGCCC GG -            #TTCCAGCA   1260                                                                 - - GAAGCTTCTC GAATACACAG ACTCCAACAA CATTGCTTCC CTCTTCCTCA CA -            #GCTGCCAA   1320                                                                 - - CAGATGGCTG GAAGTCCGAA TGGAGTACAT CGGTGCATGT GTGGTGCTCA TC -            #GCAGCGGT   1380                                                                 - - GACCTCCATC TCCAACTCCC TGCACAGGGA GCTCTCTGCT GGCCTGGTGG GC -            #CTGGGCCT   1440                                                                 - - TACCTACGCC CTAATGGTCT CCAACTACCT CAACTGGATG GTGAGGAACC TG -            #GCAGACAT   1500                                                                 - - GGAGCTCCAG CTGGGGGCTG TGAAGCGCAT CCATGGGCTC CTGAAAACCG AG -            #GCAGAGAG   1560                                                                 - - CTACGAGGGA CTCCTGGCAC CATCGCTGAT CCCAAAGAAC TGGCCAGACC AA -            #GGGAAGAT   1620                                                                 - - CCAGATCCAG AACCTGAGCG TGCGCTACGA CAGCTCCCTG AAGCCGGTGC TG -            #AAGCACGT   1680                                                                 - - CAATGCCCTC ATCTCCCCTG GACAGAAGAT CGGGATCTGC GGCCGCACCG GC -            #AGTGGGAA   1740                                                                 - - GTCCTCCTTC TCTCTTGCCT TCTTCCGCAT GGTGGACACG TTCGAAGGGC AC -            #ATCATCAT   1800                                                                 - - TGATGGCATT GACATCGCCA AACTGCCGCT GCACACCCTG CGCTCACGCC TC -            #TCCATCAT   1860                                                                 - - CCTGCAGGAC CCCGTCCTCT TCAGCGGCAC CATCCGATTT AACCTGGACC CT -            #GAGAGGAA   1920                                                                 - - GTGCTCAGAT AGCACACTGT GGGAGGCCCT GGAAATCGCC CAGCTGAAGC TG -            #GTGGTGAA   1980                                                                 - - GGCACTGCCA GGAGGCCTCG ATGCCATCAT CACAGAAGGC GGGGAGAATT TC -            #AGCCAGGG   2040                                                                 - - ACAGAGGCAG CTGTTCTGCC TGGCCCGGGC CTTCGTGAGG AAGACCAGCA TC -            #TTCATCAT   2100                                                                 - - GGACGAGGCC ACGGCTTCCA TTGACATGGC CACGGAAAAC ATCCTCCAAA AG -            #GTGGTGAT   2160                                                                 - - GACAGCCTTC GCAGACCGCA CTGTGGTCAC CATCGCGCAT CGAGTGCACA CC -            #ATCCTGAG   2220                                                                 - - TGCAGACCTG GTGATCGTCC TGAAGCGGGG TGCCATCCTT GAGTTCGATA AG -            #CCAGAGAA   2280                                                                 - - GCTGCTCAGC CGGAAGGACA GCGTCTTCGC CTCCTTCGTC CGTGCAGACA AG -            #TGACCTGC   2340                                                                 - - CAGAGCCCAA GTGCCATCCC ACATTCGGAC CCTGCCCATA CCCCTGCCTG GG -            #TTTTCTAA   2400                                                                 - - CTGTAAATCA CTTGTAAATA AATAGATTTG ATTATTTCCT AAAAAAAAAA AA - #AA             2454                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:33:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                              - - Pro Leu Ala Phe Ser Gly Thr Glu Xaa His Se - #r Ala Ala Tyr Arg Val        1               5 - #               10   - #               15                - - Asp Gln Gly Val                                                                       20                                                                - -  - - (2) INFORMATION FOR SEQ ID NO:34:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                              - - Pro Leu Ala Phe Xaa Gly Thr Glu Asn His Se - #r Ala Ala Tyr Arg Val        1               5 - #               10   - #               15                - - Asp Gln Gly Val Leu Asn Asn Gly                                                       20                                                                - -  - - (2) INFORMATION FOR SEQ ID NO:35:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  19 amin - #o acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                              - - Pro Leu Ala Phe Ser Gly Thr Glu Xaa His Se - #r Ala Ala Tyr Arg Val        1               5 - #                 10 - #                 15              - - Asp Gln Gly                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:36:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  20 amin - #o acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                              - - Xaa Leu Ala Phe Cys Gly Thr Glu Xaa His Se - #r Ala Ala Tyr Arg Val        1               5 - #                 10 - #                 15              - - Asp Gln Gly Val                                                                       20                                                                - -  - - (2) INFORMATION FOR SEQ ID NO:37:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  30 amin - #o acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                              - - Pro Leu Ala Phe Cys Gly Thr Glu Xaa His Se - #r Ala Ala Tyr Arg Val        1               5 - #                 10 - #                 15              - - Asp Gln Gly Val Leu Asn Asn Gly Cys Phe Va - #l Asp Ser Tyr                           20     - #             25     - #             30                  - -  - - (2) INFORMATION FOR SEQ ID NO:38:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  25 amin - #o acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                              - - Pro Leu Ala Phe Cys Gly Thr Glu Xaa His Se - #r Ala Ala Tyr Arg Val        1               5 - #                 10 - #                 15              - - Asp Gln Gly Val Leu Asn Asn Gly Pro                                                   20     - #             25                                         - -  - - (2) INFORMATION FOR SEQ ID NO:39:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  25 amin - #o acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                              - - Pro Leu Ala Phe Cys Gly Thr Glu Xaa His Se - #r Ala Ala Tyr Arg Val        1               5 - #                 10 - #                 15              - - Asp Gln Gly Val Leu Asn Asn Gly Cys                                                   20     - #             25                                         - -  - - (2) INFORMATION FOR SEQ ID NO:40:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  8 amino - # acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                              - - Phe Glu Gly His Ile Arg Phe Asn                                            1               5                                                            - -  - - (2) INFORMATION FOR SEQ ID NO:41:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                              - - TTCGAAGGGC ACATCCGATT TAAC          - #                  - #                    24                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:42:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  5 amino - # acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                              - - Phe Glu Asp Leu Thr                                                        1               5                                                            - -  - - (2) INFORMATION FOR SEQ ID NO:43:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                              - - TTCGAAGATT TAACC              - #                  - #                      - #    15                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:44:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                              - - TTCGAAGATT TAACC              - #                  - #                      - #    15                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:45:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 base p - #airs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                              - - GATC                 - #                  - #                  - #                  4                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:46:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                              - - CCATCCRGTG AGCC              - #                  - #                      - #     14                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:47:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                              - - CAGCCCRGCC CCCA              - #                  - #                      - #     14                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:48:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 46 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: nucleic acid                                      - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                              - - CCGGCCCCCA GCACCATCGC TGATCCCAAA GAACTGGCCA GACCAA   - #                     46                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:49:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH:  12 amin - #o acids                                               (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                              - - Ala Pro Ser Leu Ile Pro Lys Asn Trp Pro As - #p Gln                        1               5 - #                 10                                   __________________________________________________________________________

What is claimed is:
 1. A mouse whose genome comprises a homozygousdisruption in a gene encoding a sulfonylurea receptor, wherein saiddisruption comprises insertion of a nucleic acid sequence encoding aselectable marker into the gene encoding said receptor such that themouse does not produce functional receptor, and wherein said disruptionresults in a mouse that exhibits a defect in glucose regulated insulinsecretion.